Devices configured to provide treatment at an abreu brain thermal tunnel

ABSTRACT

Provided are devices for therapeutic interaction with an Abreu brain thermal tunnel (ABTT) terminus. Such devices are configured to provide one or more drugs to an ABTT terminus, and may provide heat to or remove heat from the ABTT terminus while providing the one or more drugs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.14/603,353, filed Jan. 22, 2015, which claims the benefit of priority toU.S. Provisional Patent Application No. 61/930,262, filed on Jan. 22,2014, which are hereby incorporated by reference in their entirety.

TECHNICAL FIELD

This disclosure relates to medical devices configured to monitorbiological parameters non-invasively and to provide therapeuticapplications of drugs at the skin on, over, or adjacent to an Abreubrain thermal tunnel (ABTT) terminus.

BACKGROUND

Drugs are administered by several routes, including subcutaneously,orally, intramuscular, intravenously, and transdermally. Each of theseapproaches includes drawbacks when considering the effectiveness andside effects of the drug. With the blood-brain barrier serving to keepunwanted substances out of the brain, current methods of administeringanesthesia and certain other drugs require that a very large dose of thecompound be injected into the blood stream so that the drug is receivedby the brain. As the drug travels throughout the body, the drug may beabsorbed by parts of the body not intended to intended to be exposed tothe drug, sometimes resulting in severe and adverse side effects.

Oral ingestion wastes drugs because of the passage of the drugs throughthe digestive system, in addition to the drugs being subject tofirst-pass metabolism where there is a reduced effectiveness caused byliver enzymes. In addition, these compounds may take a long time toproduce the desired effect when administered orally.

Injection allows therapeutic agents to bypass the effects of metabolism,but injections are painful and carry the risk of infection, besidesproducing large amounts of hazardous waste, e.g., used needlescontaminated with body fluid.

In addition to the drawbacks described elsewhere herein, conventionalmethods administer drugs in locations that are remote from the brain,where portions of the pharmacological effects are realized in the body,though the desired effect is in the brain.

In order to remove dependence on needles and invasive administration, amethod of transdermally introducing chemical compounds into thebloodstream via intact skin is known. Transdermal administrationdelivers drugs or other chemicals through the skin to local tissue, andthen into the systemic circulatory system without cutting or penetrationof the skin. Using transdermal methods rather than injections reducespain, biohazardous waste, and risk of infection. Currently, transdermaldelivery systems have been proposed or developed for a variety of drugsor therapeutic agents to treat many conditions and diseases.

While transdermal delivery of drugs presents many potential benefits andwide applications, its development is limited due to the biologicalnature of the skin, which presents a barrier to penetration because thelow permeability of the skin limits the application of transdermaldelivery. The transdermal flux of a drug depends on the diffusioncoefficient of the drug; the thickness of the epidermis and dermis, andthe condition of the skin at the application site; and the concentrationgradient across the skin.

Passive transdermal delivery methods comprise the use of patches thatcontain a drug, and often a permeation enhancer. The structure oftransdermal delivery patches generally comprises an outer layer, amiddle layer that contains the drug, and a liner and/or a release linerthat protects the adhesive layer, which is removed prior to use.

As briefly described above, transdermal delivery of active agents isgenerally executed in an area of the body that is remote from the brainor active control center that is affected by the drug being introducedinto the body such as, for example, the arm, buttock, back, or leg. Allof the areas currently used for transdermal delivery have a great dealof adipose tissue, i.e., fat, which serves as a significant barrier totransdermal delivery of therapeutic agents. These sites presentlimitations to the transdermal delivery methods, as a high dosage mustbe used to ensure that an effective dose reaches the control centerdesigned to be treated by the drug. Excess drugs and active agentscirculating throughout the body may be absorbed by organs and tissuesnot intended to be treated, thus resulting in an increased risk fordamaging side effects. For this reason especially, transdermal deliveryis extremely limited or impossible for use with potent drugs.

SUMMARY

This disclosure provides a series of interfaces. The interface maycomprise a layer facing the ABTT skin that includes an adhesive havingpores, holes and the like. Adjacent to this adhesive layer is amedication-containing layer or alternatively a reservoir housingmedication. In an exemplary embodiment, the present disclosure includesan interface having a reservoir housing an absorbent material such as asponge, a pad, a gel, and the like, said absorbent material being soakedwith a solution of a medication, said absorbent material preferablybeing compressible. It is understood that the reservoir may includeliquid, solution, cream, paste, and the like, or a combination thereof.In another embodiment, the aforementioned medication is applied througha membrane-like surface. It is also understood that the interface doesnot need to have an adhesive layer facing the skin and is positionedagainst the skin without adhesive by means of a mechanism applyingpressure. Medication referred herein includes any chemical compound.

In an exemplary embodiment, the interface contacts the skin of the ABTTand may include additional adjacent areas, wherein medication isadministered through a layer in contact with said skin of the ABTT. Inanother exemplary embodiment, the interface contacts the skin overlyingthe veins associated with the ABTT and may include adjacent areas, asdisclosed herein, wherein medication is administered through a layer incontact with said skin. In another exemplary embodiment, the interfacecontacts a combination of the skin of the ABTT and the skin overlyingthe veins associated with the ABTT and may include adjacent areas. Inexemplary embodiments, the adjacent areas range from greater than zeroto 35 mm from the center of the ABTT.

The dimensions of the interface in contact with the skin preventunwanted thermal stimulation of the skin and also prevent delivery ofmedication away from the target areas, namely the ABTT skin and/or skinoverlying the veins associated with the ABTT. By isolating the area, theeffect of the medication is increased and side effects are decreased oreliminated.

In one exemplary embodiment, the interface may comprise a multi-layerstructure, including an outer layer that can function as a waterrepellent. In one exemplary embodiment, the interface may include anadjustable arm, said adjustable arm being preferably connected to aframe, including but not limited to a frame of eyeglasses, goggles, eyemask, head-gear, neck-gear, and the like. It should be understood thatthe arm may be connected by a support structure having an adhesivesurface, said adhesive functioning as an anchoring means, not as a drugdelivery means. The arm is constructed of suitably flexible materials,so as to be able to bend and be positioned against the ABTT skin.

In one exemplary embodiment, the interface can have any shape,including, but not limited to, oval, rectangular, square, oblong, andthe like. In another exemplary embodiment, the interface can furtherinclude a releasable liner.

In one exemplary embodiment, the interface is constructed with at leastone outer impermeable layer such as polyethylene, polyester, and thelike.

In one exemplary embodiment, the adhesive surface includes medical gradeadhesive, pressure sensitive adhesive, and the like.

In one exemplary embodiment of the interface, the medication ispreferably contained in a mid-portion bordered by an outer cover orlayer.

In one exemplary embodiment, the support device may include a flexiblecircuit and thermoelectric devices preferably spaced from each other.

The interface includes a surface that is permeable to allow diffusion ofthe medication.

By having an interface that relies on pressure mechanisms, the presentdisclosure provides embodiments that eliminate the drawbacks andlimitations of using adhesives, such as discomfort, skin maceration,residues on the skin after removal and the like.

Advantages and features of the embodiments of this disclosure willbecome more apparent from the following detailed description ofexemplary embodiments when viewed in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a simplified view of the ABTT and facial veins associated withthe ABTT.

FIG. 2A is a simplified partial cross-sectional view through a humanskull in a vertical direction, showing the Abreu brain thermal tunneland certain other facial features.

FIG. 2B is a simplified view of the ABTT area and veins associated withthe ABTT area.

FIG. 3 is a stylized representation of the flow of blood into a braincore.

FIG. 4 is a plan view of a passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 5 is a plan view of another passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 6 is a cross-sectional view of the passive transdermal deliverydevice of FIG. 4 along the lines 6-6.

FIG. 7 is a perspective view of yet another passive transdermal deliverydevice in accordance with an exemplary embodiment of the presentdisclosure.

FIG. 8 is a plan view of a general configuration of passive transdermaldelivery devices in accordance with an exemplary embodiment of thepresent disclosure.

FIG. 9 is a view of two overlapping circles used to define the limits ofa transdermal delivery device in accordance with an exemplary embodimentof the present disclosure.

FIG. 10 is a view of two non-overlapping circles used to define thelimits of a transdermal delivery device in accordance with an exemplaryembodiment of the present disclosure.

FIG. 11 is a view of a further transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure positioned on asubject or patient's face.

FIG. 12 is a plan view of a yet further transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 13 is a cross-sectional view of the transdermal delivery device ofFIG. 12 along the lines 13-13.

FIG. 14 is a plan view of another transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 15 is a cross-sectional view of the transdermal delivery device ofFIG. 14 along the lines 15-15.

FIG. 16 is a cross-sectional view of a transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure, alongthe lines 16-16 in FIG. 17, as though the device in FIG. 17 were whole.

FIG. 17 is a cross-sectional view of the transdermal delivery device ofFIG. 16 along the lines 17-17, as though the device in FIG. 16 werewhole.

FIG. 18 is a plan view of a transdermal delivery device configured toinclude two drug containers, in accordance with an exemplary embodimentof the present disclosure.

FIG. 19 is a plan view of a transdermal delivery device configured toinclude three drug containers, in accordance with an exemplaryembodiment of the present disclosure.

FIG. 20 is a plan view of a transdermal delivery device, in accordancewith an exemplary embodiment of the present disclosure.

FIG. 21 is a plan view of a transdermal delivery device positioned on aface of a subject or patient, in accordance with an exemplary embodimentof the present disclosure.

FIG. 22 is a perspective view of a transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 23 is a view of a patient or subject's face with the transdermaldelivery device of FIG. 22 positioned on the patient or subject's ABTTterminus.

FIG. 24 is a side view of a patient or subject's face with a pluralityof transdermal delivery devices positioned thereon, in accordance withan exemplary embodiment of the present disclosure.

FIG. 25 is a view of a patient or subject's face with a transdermaldelivery device in accordance with an exemplary embodiment of thepresent disclosure positioned thereon.

FIG. 26 is a view of a patient or subject's face with anothertransdermal delivery device in accordance with an exemplary embodimentof the present disclosure positioned thereon.

FIG. 27 is a view of a patient or subject's face with yet anothertransdermal delivery device in accordance with an exemplary embodimentof the present disclosure positioned thereon.

FIG. 28 is a view of a patient or subject's face with a furthertransdermal delivery device in accordance with an exemplary embodimentof the present disclosure positioned thereon.

FIG. 29 is a view of a patient or subject's face with a still furthertransdermal delivery device in accordance with an exemplary embodimentof the present disclosure positioned thereon.

FIG. 30 is a view of a passive transdermal delivery device configured tosimultaneously delivery two different drugs, in accordance with anexemplary embodiment of the present disclosure.

FIG. 31 is a plan view of a further passive transdermal delivery device,in accordance with an exemplary embodiment of the present disclosure.

FIG. 32 is a cross-sectional view of the passive transdermal deliverydevice of FIG. 31 along the lines 32-32.

FIG. 33 is a view of a patient or subject with the passive transdermaldelivery device of FIGS. 31 and 32 positioned thereon.

FIG. 34 is a cross-sectional view of a passive transdermal deliverydevice that includes an enhanced drug delivery feature, in accordancewith an exemplary embodiment of the present disclosure.

FIG. 35 is a view of a subject or patient's face with a passivetransdermal delivery device in accordance with an exemplary embodimentof the present disclosure fixed thereto.

FIG. 36 is a view of the transdermal delivery device of FIG. 35.

FIG. 37 is a view of a device support for the transdermal deliverydevice of FIG. 36.

FIG. 38 is a view of another transdermal delivery device and supportdevice in accordance with an exemplary embodiment of the presentdisclosure.

FIG. 39 is a view of the transdermal delivery device of FIG. 38 alongthe lines 39-39.

FIG. 40 is a view of a passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure.

FIG. 41 is a view of a passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure, positioned on anABTT terminus.

FIG. 42 is a view of a passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure incorporated inan eyeglass frame.

FIG. 43 is a view of a passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure configured as anose clip.

FIG. 44 is a view of another passive transdermal delivery deviceconfigured as a nose clip in accordance with an exemplary embodiment ofthe present disclosure.

FIG. 45 is a view of a handheld passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 46 is a view or a portion of the transdermal delivery device ofFIG. 45.

FIG. 47 is a view of a passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure.

FIG. 48 is a view of a transdermal delivery device in accordance with anexemplary embodiment of the present disclosure.

FIG. 49 is a view of a transdermal delivery device in accordance with anexemplary embodiment of the present disclosure.

FIG. 50 is a view of a transdermal delivery device in accordance with anexemplary embodiment of the present disclosure.

FIG. 51 is a view of a transdermal delivery device in accordance with anexemplary embodiment of the present disclosure.

FIG. 52 is a view of a transdermal delivery system in accordance with anexemplary embodiment of the present disclosure.

FIG. 53 is a view of an active transdermal delivery system in accordancewith an exemplary embodiment of the present disclosure.

FIG. 54 is a view of another active transdermal delivery system inaccordance with an exemplary embodiment of the present disclosure.

FIG. 55 is a view of yet another active transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 56 is a cross-sectional view of the active transdermal deliverydevice of FIG. 55 along the lines 56-56.

FIG. 57 is a view of a passive transdermal delivery module in accordancewith an exemplary embodiment of the present disclosure.

FIG. 58 is a view of an active transdermal delivery module in accordancewith an exemplary embodiment of the present disclosure.

FIG. 59 is a view of another active transdermal delivery module inaccordance with an exemplary embodiment of the present disclosure.

FIG. 60 is a view of yet another active transdermal delivery module inaccordance with an exemplary embodiment of the present disclosure.

FIG. 61 is a view of a basic active transdermal delivery system inaccordance with an exemplary embodiment of the present disclosure.

FIG. 62 is a view of a drug delivery interface including a spring, inaccordance with an exemplary embodiment of the present disclosure.

FIG. 63 is a view of an active transdermal delivery device configured todeliver two drugs, in accordance with an exemplary embodiment of thepresent disclosure.

FIG. 64 is a view of another active transdermal delivery deviceconfigured to deliver two drugs, in accordance with an exemplaryembodiment of the present disclosure.

FIG. 65 is a first graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure.

FIG. 66 is a second graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure.

FIG. 67 is a third graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure.

FIG. 68 is a fourth graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure.

FIG. 69 is a fifth graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure.

FIG. 70 is a sixth graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure.

FIG. 71 is a seventh graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure.

FIG. 72 is an exterior view of an active transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 73 is an interior view of the active transdermal delivery device ofFIG. 72.

FIG. 74 is a perspective view of an active transdermal delivery devicein accordance with an exemplary embodiment of the present disclosure.

FIG. 75 is a perspective view of another active transdermal deliverydevice in accordance with an exemplary embodiment of the presentdisclosure.

FIG. 76 is a perspective view of yet another active transdermal deliverydevice in accordance with an exemplary embodiment of the presentdisclosure.

FIG. 77 is a view of an active transdermal delivery device in the formof a nose clip, in accordance with an exemplary embodiment of thepresent disclosure.

FIG. 78 is a cross-sectional view of an active transdermal deliverydevice connected to a separate reservoir, in accordance with anexemplary embodiment of the present disclosure.

FIG. 79 is a cross-sectional view of an active transdermal deliverydevice configured to provide two types of drug release, in accordancewith an exemplary embodiment of the present disclosure.

FIG. 80 is a perspective view of a portion of a frame configured toinclude a removable reservoir, in accordance with an exemplaryembodiment of the present disclosure.

FIG. 81 is a cross-sectional view of the frame of FIG. 80 along thelines 81-81, with the removable reservoir installed in the frame.

FIG. 82 is a cross-sectional view of the frame of FIGS. 80 and 81, alongthe lines 82-82.

FIG. 83 is a perspective view of a separate drug reservoir in accordancewith an exemplary embodiment of the present disclosure.

FIG. 84 is a perspective view of a mask incorporating an activetransdermal delivery system in accordance with an exemplary embodimentof the present disclosure.

FIG. 85 is a perspective view of a portion of the active transdermaldelivery system of FIG. 84.

FIG. 86 is a cross-sectional view of the portion of FIG. 85 along thelines 86-86.

FIG. 87 is a perspective view of a puncture or penetrating device ofFIG. 86, in accordance with an exemplary embodiment of the presentdisclosure.

FIG. 88 is a perspective view of a puncture or penetrating device ofFIG. 86, in accordance with an exemplary embodiment of the presentdisclosure.

FIG. 89 is a view of a transdermal delivery system in accordance with anexemplary embodiment of the present disclosure.

FIG. 90 is a process flow of the system of FIG. 89 in accordance with anexemplary embodiment of the present disclosure.

FIG. 91 is another process flow of the system of FIG. 89 in accordancewith an exemplary embodiment of the present disclosure.

FIG. 92 is another transdermal delivery system in accordance with anexemplary embodiment of the present disclosure.

FIG. 93 is a process flow of the system of FIG. 92.

FIG. 94 is a view of a retroauricular drug delivery device in accordancewith an exemplary embodiment of the present disclosure.

FIG. 95 is a view of another retroauricular drug delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 96 is a view of yet another retroauricular drug delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 97 is a view of a further retroauricular drug delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 98 is a view of a yet further retroauricular drug delivery devicein accordance with an exemplary embodiment of the present disclosure.

FIG. 99 is a view of still another retroauricular drug delivery devicein accordance with an exemplary embodiment of the present disclosure.

FIG. 100 is a view of a tear diagnostic system in accordance with anexemplary embodiment of the present disclosure.

FIG. 101 is a view of another tear diagnostic system in accordance withan exemplary embodiment of the present disclosure.

FIG. 102 is a view of yet another active transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 103 is a view of a face showing locations for application ofpassive or active transdermal delivery devices, in accordance with anexemplary embodiment of the present disclosure.

FIG. 104 is a view of a face showing additional locations available forplacement of an active or a passive transdermal delivery device, inaccordance with an exemplary embodiment of the present disclosure.

FIG. 105 is a schematic view of an active transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 106 is a graph showing a comparison of a chemical absorptionthrough an arm patch and a patch on the ABTT terminus

FIG. 107 is a perspective view of another transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure.

FIG. 108 is a view of a transdermal delivery device in accordance withan exemplary embodiment of the present disclosure.

FIG. 109 is a view of a transdermal delivery device in accordance withan exemplary embodiment of the present disclosure.

FIG. 110 is a view of a transdermal delivery system in accordance withan exemplary embodiment of the present disclosure.

FIG. 111 is a view of a transdermal delivery system in accordance withan exemplary embodiment of the present disclosure.

FIG. 112 is a view of a transdermal delivery system in accordance withan exemplary embodiment of the present disclosure.

FIG. 113 is a view of another transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure.

FIG. 114 is a view of the transdermal delivery device of FIG. 113,illustrating the operation of the device.

FIG. 115 is a view of an animal wearing a transdermal delivery system inaccordance with an exemplary embodiment of the present disclosure

FIG. 116 is a view of an animal wearing another transdermal deliverysystem in accordance with an exemplary embodiment of the presentdisclosure.

FIG. 117 is a view of an intracranial thermal path interface inaccordance with an exemplary embodiment of the present disclosure.

FIG. 118 is a view of a drug container of the interface of FIG. 117.

FIG. 119 is a cross-sectional view of the drug container of FIG. 118along the lines 119-119.

FIG. 120 is a cross-sectional view of another intracranial thermal pathinterface in accordance with an exemplary embodiment of the presentdisclosure.

FIG. 121 is a view of a transdermal delivery device positioned on a headof a subject or patient in accordance with an exemplary embodiment ofthe present disclosure.

FIG. 122 is a view of the transdermal delivery device of FIG. 121.

FIG. 123 is a perspective view of an iontophoretic system in accordancewith an exemplary embodiment of the present disclosure.

FIG. 124 is a view of a portion of the iontophoretic system of FIG. 123.

FIG. 125 is a cross-sectional view of the iontophoretic system of FIGS.123 and 124.

FIG. 126 is a view of an arm of iontophoretic system in accordance withan alternative embodiment of the present disclosure.

FIG. 127 is a view of a portion of an iontophoretic system in accordancewith an exemplary embodiment of the present disclosure.

FIG. 128 is a view of another iontophoretic system in accordance with anexemplary embodiment of the present disclosure.

FIG. 129 is a view of yet another iontophoretic system in accordancewith an exemplary embodiment of the present disclosure.

DETAILED DESCRIPTION

The present disclosure arises from the discovery that an Abreu brainthermal tunnel or ABTT provides the first known structure forbrain-surface thermodynamic communication and thermal connectiondirectly with the center of the brain. Anatomically and physiologicallyspeaking, and as shown in FIGS. 1-3, ABTT 12 includes a continuous,direct, and undisturbed connection between a brain core 24 at thecontrol center of the brain and the skin of ABTT terminus 10. The skinof ABTT terminus 10 is unique in that it is the thinnest skin with thefewest layers, a fat layer is absent, and has the high thermalconductivity of any skin on the human body.

The physical and physiological events at one end of the tunnel arereproduced at the opposite end. ABTT 12 enables the direct transfer ofinputs to ABTT 12 to brain core 24 without significant barriers, asdescribed in co-pending U.S. patent application Ser. No. 14/512,421,filed on Oct. 11, 2014, incorporated by reference herein in itsentirety. Accordingly, the present disclosure describes apparatus,systems, devices, mechanisms, and methods that use ABTT terminus 10 andABTT 12 to delivery compounds, chemicals, medications, biologics, suchas vaccines and genes, and drugs to the brain core.

Anatomy shows the convergence of four veins at ABTT target area 10:frontal 14, superior palpebral 16, supraorbital 18, and angular 20. Asangular vein 20 extends further from ABTT 12, it transitions into facialvein 22. Having converged, the blood from these veins flows toward braincore 24 from ABTT target area 10 between an eye 31 and the eyebrow intothe center of the brain, which is the temperature center present in thehypothalamus or thermal storage area of the body present in thecavernous sinus. From the thermal storage area, blood is distributedthroughout the brain tissue and the body, and may be used to effectivelyand efficiently treat and/or prevent medical conditions by thetransmission of medications, chemicals, and compounds to the brain.

FIGS. 1, 2A, and 2B show the approximate location of these veins inrelation to other facial features. Angular/facial vein 20/22 runs upalongside nose 26, superior palpebral vein 16 runs along eyebrow 28, andfrontal vein 14 and supraorbital vein 18 run through forehead 30.Delivery of medication to these veins, and particularly ABTT terminus10, provides a path between the skin and brain core 24 with the leastbarrier or resistance to drug transport identified in the human body.For the purposes of disclosure, terminology referring to relevant facialareas or veins herein will be described as one or more of theabove-referenced veins and ABTT target area 10.

As described herein, veins 14, 16, 18, 20, and 22 converge in thesuperomedial orbit in the region of the upper eyelid and adjacent to thebridge of the nose, and flow directly, without inhibition, to the centerof the brain. The skin in this area, as shown in pending application bythe Applicant, is the thinnest skin in the body and free of fat,providing thereby the area most permeable to administering drugs, and bybeing in direct communication with the brain, the most direct path fordrug delivery to the brain. These vessels lack valves, which aretypically an important barrier to flow and direct transmission ofpharmacologically agents. Without valves, these blood vessels trulyprovide a direct, uninhibited passage for transporting therapeuticagents directly to the hypothalamic region of the brain. Moreover, ABTT12 includes a superior ophthalmic vein (SOV) 23, which connects the skinsurface to the brain and corresponds to the central portion of thetunnel (ABTT 12), is valveless and has bidirectional blood flow. The SOVlies directly underneath the skin of the superomedial orbit, between eye31 and eyebrow, and is a direct conduit from surface to the brain to thehypothalamus. The hypothalamic region of the brain is the link betweenthe central nervous system and the endocrine system and, as such, actsas the center of control for many basic bodily functions such as, forexample, hunger, thirst, body temperature, fatigue, blood pressure,immune responses, circadian cycles, hormone production and secretion,and many others.

As shown in, for example, FIG. 2B, the facial end of ABTT 12, hereinreferred to as a target area, or terminus 10 on the skin on, over, oradjacent to ABTT 12, measures about 11 mm in diameter measured from themedial corner of eye 31 at the medial canthal tendon and extendssuperiorly for about an additional 6 or 7 mm in an ABTT superiorprojection 11, and then extends into an upper eyelid 15 in a horn-likeprojection 13 for another 22 mm. ABTT terminus 10 is absent fat, andABTT superior project 11 and horn-like project 13 are absent fat inareas near to ABTT terminus 10, with a fat layer present in areas aspaced distance away from ABTT terminus 10. It should be understood thatthe dashed lines in FIG. 2B represent features under the skin, andfacial features are shown for approximate reference.

ABTT target area 10, as described herein, provides a direct link to thecontrol center of the brain, since the skin of ABTT target area 10 isfree from adipose tissue and other barriers. Because the blood vesselscarrying blood into the brain are superficial and lie just under the toplayer of thin skin, ABTT target area or terminus 10 is the ideallocation for transdermal delivery to occur. In fact, the direct flow tothe brain may allow doses of drugs and other chemical compoundsdelivered transdermally to be reduced drastically. These lower dosesmay, in turn, reduce the side-effects involved with many drugs, decreasewaiting time before the effects of a drug are noticed, increaseeffectiveness of certain drugs, and remove the necessity for invasiveand painful use of needles. Also, transdermal delivery of many drugs mayno longer need to be carried out remotely. Since drugs can reach thehypothalamus and brain directly, the apparatus and method of the presentdisclosure may be used for treatment of numerous diseases and conditionsthat are regulated by the center of the brain such as, by way ofillustration, but not of limitation, Alzheimer's disease, Parkinson'sdisease, thyroid conditions, seizures, pain, and hunger. Examples ofdrugs that may be administered using this method are contraceptives,anesthesia, antibiotics, narcotics, any hormonal associated drugs,cancer agents, and any drug to treat any condition or disease.

The present disclosure concerns a device, apparatus, or mechanism andmethod for transdermally delivering drugs and other chemical compoundsor therapeutic agents through the skin of ABTT target area 10.

In one example of an application of the present disclosure, as carriedout in a research setting, a patch designed to transdermally delivermelatonin (MEL] through the skin of ABTT target area 10 was shown toprovide an intended therapeutic effect. Oral introduction of MEL issuggested to elevate plasma MEL and reduce waking after sleep onset bypromoting sleep in the latter part of an 8-hour sleep opportunity. MELhas been shown to improve daytime sleep, but the hormone's shortelimination half-life limits its use as a hypnotic in shift workers andindividuals with jet lag or other sleep problems. As a solution to thisproblem, MEL was applied transdermally on the skin of ABTT target area10 using a patch that contained, in a solvent formulation, water,propylene glycol, lauric acid, and hydroxypropylcellulose, and alsocomprised a non-rate-limiting membrane designed to have active contactwith an area 1.0 cm². Experiments show that ABTT terminus 10 and thedose were best suited to produce the intended plasma profile forclinical effect. It should be understood that any type of membrane orporous material can be used in accordance with the principles of thepresent disclosure.

In the present disclosure, the terms therapeutic agent, medication,compound, and drug are used to describe any compound, molecule,solution, element or other chemical intended to be intentionallypresented into the body to provide an intended benefit. Most often, thepresent disclosure is intended for use in conjunction with drugsprescribed by a doctor or the like and intended to treat a certaincondition such as, for example, pain or a disease. However, it should beunderstood that the present disclosure is not limited to the examplesherein or for use with common drugs or to treat specific diseases. Forexample, although it may not be preferred, the present disclosure may beused in conjunction with any chemical compound to include even drugssuch as cocaine, cannabis, lysergic acid, amphetamines, and the like. Itshould also be understood that homeopathic drugs, and drugs that areused in minimal concentrations or amounts, are also within the scope ofthe present invention. It should also be understood that any naturallyoccurring substance, such as, by way of illustration, any vegetables,including garlic, caffeine, and the like, as well as any type ofvitamins, energizing compounds, nutritional compounds, food compounds,and the like, are within the scope of the invention. Although anychemical compound or any drug can be administered according to theprinciples of the present invention, examples of drugs that may bedelivered by devices according to this disclosure include, but are notlimited to, prochlorperzine edisylate, ferrous sulfate, aminocaproicacid, mecamylamine hydrochloride, procainamide hydrochloride,amphetamine sulfate, methamphetamine hydrochloride, benzamphetaminehydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride,bethanechol chloride, methacholine chloride, pilocarpine hydrochloride,atropine sulfate, scopolamine bromide, isopropamide iodide,tridihexethyl chloride, phenformin hydrochloride, methyiphenidatehydrochloride, theophylline cholinate, cephalexin hydrochloride,diphenidol, meclizine hydrochloride, prochiorperazine maleate,phenoxybenzamine, thiethylperzine maleate, anisindone, diphenadioneerythrityl tetranitrate, digoxin, isofluorphate, acetazolamide,methazolamide, bendroflumethiazide, chloropromaide, tolazamide,chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin,methotrexate, acetyl sulfisoxazole, erythromycin, hydrocortisone,hydrocorticosterone acetate, cortisone acetate, dexamethasone and itsderivatives such as betamethasone, triamcinolone, methyltestosterone,17-.beta.-Estradiol, ethinyl estradiol, ethinyl estradiol 3-methylether, prednisolone, 17-.alpha.-hydroxyprogesterone acetate,19-nor-progesterone, norgestrel, norethindrone, norethisterone,norethiederone, progesterone, norgesterone, norethynodrel, aspirin,indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin,isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol,cimetidine, clonidine, imipra mine, levodopa, chlorpromazine,methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate,ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac,ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem,milrinone, capropril, mandol, quanbenz, hydrochiorothiazide, ranitidine,flubiprofen, fenufen, fluprofen, tolmetin, aicofenac, mefenamic,flufenamic, difiuinal, nimodipinefnitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinoipril, enalapril, enalaprilat, captopril, ramiprii,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chiordiazepoxide, diazepam, amitriptyline, and imipramine. Furtherexamples are proteins and peptides that include, but are not limited to,insulin, colchicine, glucagon, thyroid-stimulating hormone, parathyroidand pituitary hormones, calcitonin, rennin, prolactin, corticotrophin,thyrotropic hormone, follicle-stimulating hormone, chorionicgonadotropin, gonadotropin-releasing hormone, bovine somatotropin,porcine somatotropin, oxytocin, vasopressln, GRF, somatostatin,lypressin, pancreozymin, luteinizing hormone, LHRH, LHRH agonists andantagonists, leuprolide, interferons (including alpha, beta, delta, andgamma), interleukins, growth hormones such as human growth hormone,bovine growth hormone and porcine growth hormone, fertility inhibitorssuch as the prostaglandins, fertility promoters, growth factors,coagulation factors, human pancreas hormone-releasing factor, analogsand derivatives of these compounds, and pharmaceutically acceptablesalts of these compounds, or their analogs or derivatives.

Some exemplary embodiments of the present disclosure are intended forthe transdermal delivery of drugs, therapeutic agents, or other chemicalcompounds into the body through ABTT target area 10 using the teachingsof the exemplary embodiments of the present disclosure.

In an exemplary embodiment, a passive type apparatus of the presentdisclosure in an exemplary embodiment includes a housing containing adrug or other compound that has a protective backing and is adapted tobe secured to ABTT target area 10, which in an exemplary embodiment maybe accomplished by using an adhesive material, such as a patch deliverymethod described in detail herein. The patch may be configured forone-time use to deliver a single dose of medication or it may comprise aliner that is adapted to release a specific amount of compound over anextended period of time, or to release several doses of medication overa further prolonged period of time. In alternate embodiments, thepassive apparatus may also employ the use of any permeation enhancers orother topical passive permeation methods as described in detail herein.The patch can also be reusable and used for certain period of time andthen removed. In this embodiment, a new adhesive surface may be used tosecure the patch to the skin. The chemical compound can also be replacedonce the original compound has been delivered to the skin in itsentirety.

As described herein, the present disclosure describes apparatus,devices, mechanisms, systems, and methods of delivering compounds,chemicals, and drugs to the brain core. For the sake of simplicity, allsubstances deliverable to the brain core are described herein as“drugs.” Generally, devices for delivering drugs through ABTT terminus10 can be categorized as passive devices, which operate by the presenceof the drug on the skin of ABTT terminus 10 and/or associated veins 14,16, 18, 20 and 22, or active devices, which include one or more featuresto control drug delivery to ABTT terminus 10 and/or associated veins 14,16, 18, 20 and 22, or to control drug flow through ABTT terminus 10and/or associated veins 14, 16, 18, 20 and 22. Generally, theconfigurations and dimensions shown for passive transdermal devices canbe applied to active transdermal devices, and vice versa, when an activeor passive embodiment can be configured with such configurations anddimensions, unless otherwise specified.

Passive transdermal delivery devices are configured to deliver preciseamounts of drugs to ABTT terminus 10 and/or the skin over associatedveins 14, 16, 18, 20, and 22, for permeation through the skin at ABTTterminus 10 and/or associated veins 14, 16, 18, 20, and 22, andsubsequent transmission through ABTT 12 to brain core 24. While thevarious embodiments of transdermal delivery devices disclosed hereinbear similarity to conventional passive transdermal patches, a pluralityof differences exist, as will be understood by a person of ordinaryskill in that art reading and applying the teachings of the presentdisclosure.

Many aspects of the disclosure are described in terms of sequences ofactions to be performed by elements of a computer system or otherhardware capable of executing programmed instructions, for example, ageneral purpose computer, special purpose computer, workstation, orother programmable data processing apparatus. It will be recognized thatin each of the embodiments including active or electronic elements, thevarious actions could be performed by specialized circuits (e.g.,discrete logic gates interconnected to perform a specialized function),by program instructions (software), such as logical blocks, programmodules etc. being executed by one or more processors (e.g., one or moremicroprocessors, a central processing unit (CPU), and/or applicationspecific integrated circuit), or by a combination of both. For example,embodiments can be implemented in hardware, software, firmware,middleware, microcode, or any combination thereof. The instructions canbe program code or code segments that perform necessary tasks and can bestored in a non-transitory, machine-readable medium such as a storagemedium or other storage(s). A code segment may represent a procedure, afunction, a subprogram, a program, a routine, a subroutine, a module, asoftware package, a class, or any combination of instructions, datastructures, or program statements. A code segment may be coupled toanother code segment or a hardware circuit by passing and/or receivinginformation, data, arguments, parameters, or memory contents.

The non-transitory machine-readable medium can additionally beconsidered to be embodied within any tangible form of computer readablecarrier, such as solid-state memory, magnetic disk, and optical diskcontaining an appropriate set of computer instructions, such as programmodules, and data structures that would cause a processor to carry outthe techniques described herein. A computer-readable medium may includethe following: an electrical connection having one or more wires,magnetic disk storage, magnetic cassettes, magnetic tape or othermagnetic storage devices, a portable computer diskette, a random accessmemory (RAM), a read-only memory (ROM), an erasable programmableread-only memory (e.g., EPROM, EEPROM, or Flash memory), or any othertangible medium capable of storing information.

It should be noted that the systems of the present disclosure areillustrated and discussed herein as having various modules and unitswhich perform particular functions. It should be understood that thesemodules and units are merely schematically illustrated based on theirfunction for clarity purposes, and do not necessarily represent specifichardware or software. In this regard, these modules, units and othercomponents may be hardware and/or software implemented to substantiallyperform their particular functions explained herein. The variousfunctions of the different components can be combined or segregated ashardware and/or software modules in any manner, and can be usefulseparately or in combination. Input/output or I/O devices or userinterfaces including but not limited to keyboards, displays, pointingdevices, and the like can be coupled to the system either directly orthrough intervening I/O controllers. Thus, the various aspects of thedisclosure may be embodied in many different forms, and all such formsare contemplated to be within the scope of the disclosure.

Basic passive transdermal delivery devices are shown in FIGS. 4-6. Afirst configuration of a passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure isshown in FIGS. 4 and 6, indicated generally at 32. In the embodiment ofFIG. 4, passive device 32 includes a first portion 34, which may also bedescribed as a drug container or reservoir, and a second portion 36,which may also be described as a border or edge.

Device 32 is configured to include dimensions that are optimized forinterfacing with ABTT terminus 10. In an exemplary embodiment, device 32is configured with a device diameter 38 of less than or equal to about25 mm. In this exemplary embodiment, drug container 34 includes adiameter 40 of less than or equal to 15 mm. However, in anotherexemplary embodiment, drug container diameter 40 can also be less thanor equal to 10 mm, and in yet another exemplary embodiment, drugcontainer diameter 40 can be less than or equal to 7.5 mm. In yetanother exemplary embodiment, device diameter 38 can be less than orequal to 30 mm, and drug container diameter 40 can be less than or equalto 20 mm, less than or equal to 15 mm, less than or equal to 10 mm, orless than or equal to 7.5 mm. In a further exemplary embodiment, devicediameter 38 can be less than or equal to 20 mm, and drug containerdiameter 40 can be less than or equal to 10 mm, or less than or equal to7.5 mm. In yet a further exemplary embodiment, device diameter 38 can beless than or equal to 10 mm, and drug container diameter 40 can be lessthan or equal to 2.5 mm. The area outside drug containing area 34 isreferred as an edge or border 41, and the dimension of edge or border 41is associated with the strength of the adhesive. Therefore, an edge witha strong adhesive can be made very small, such as including a width thatis equal to or less than 1 mm, for example, and in this embodiment drugcontaining area 34 can have a diameter (or largest dimension) in a rangefrom 1 mm to 40 mm. It should be noted that the whole surface area(identified as diameter 38) can be covered by an adhesive surface, withthe drug disposed behind this surface, and in this embodiment the wholearea contains drug and there is not a separate edge with adhesive.

Dimensions of the surface containing drug of the embodiments of thepresent disclosure can be made smaller as compared to traditionalpatches or devices because less drug is necessary since ABTT terminus 10area has the highest permeation rate of the body and there is a directcommunication with the blood vessels and direct path to the brain.

The larger diameter 40 of drug container 34 becomes, the easier it is toassure drug placement on ABTT terminus 10. However, the larger diameter40 becomes, the more uncontrolled delivery of drugs becomes.Accordingly, smaller diameters 40 are preferred for controlled,efficient delivery of drugs located in drug container 34 to ABTTterminus 10. However, a minimum diameter 40 is preferred because thediameter of ABTT terminus 10 is approximately 3 mm to 11 mm, used todefine the diameter, and as will be seen, beyond ABTT terminus 10 alayer of fat under the skin reduces the flow rate of drugs into ABTT 12.

The larger diameter 38 of device 32 becomes, the easier it is to handleand place device 32. However, diameter 38 is practically determined byan adjacent eye of a patient or subject, since ABTT terminus 10 is verynear to the eye, and most patients or subjects object to the placementof objects on or over the eye. Accordingly, a smaller diameter 38 ispreferred for patient comfort, but the smaller diameter 38 becomes, themore difficult it is to handle and place device 32.

FIG. 6 shows an exemplary cross section of device 32 of FIG. 4. Device32 includes at least a backing or support layer 42 on which ispositioned, either directly or indirectly, a protective layer 44. A drug46 is positioned directly between protective layer 44 and backing layer42. Protective layer 44 and backing layer 42 may be configured to beimpermeable to drug 46, or additional layers may be provided in device32 to protect protective layer 44 and backing layer 42 from drug 46, orto control flow of drug 46 out of device 32. In an exemplary embodiment,an adhesive layer 48 is also positioned between protective layer 44 andbacking layer 42. Adhesive layer 48 is configured to secure device 32 toa patient or subject's skin to permit drug 46 to be directly in contactwith the patient or subject's skin to permit the permeation of the skinby drug 46. In an exemplary embodiment, drug 46 is infused into adhesivelayer 48, and removal of protective layer 44 exposes adhesive layer 48and drug 46 such that an exemplary device 32 is configured to be securedto a patient or subject's skin across the entirety of device 32 byadhesive layer 48.

In the exemplary embodiment of FIG. 7, device 32 is configured toinclude a convex curvature 50. Curvature 50 is configured to be anapproximate match to the unique curvature of the face at ABTT terminus10. It should also be understood that each of the disclosed embodimentscan or does include a similar curvature to match the area on andadjacent to ABTT terminus 10. It should also be understood that a flatpatch or device, including a conventional flat patch or flat bandage arewithin the scope of the invention. A flat patch or flat device includesflexible areas, or can be flexible in its entirety so as to conform tothe geometry and shape of the ABTT terminus 10.

FIG. 5 is a view of another passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 52. Device 52 is configured to be approximatelysquare in a plan view. Similar to device 32, device 52 includes a firstportion 54, which may also be described as a drug container orreservoir, and a second portion 56, which may also be described as aborder or edge.

Similar to device 32, device 52 is configured to include dimensions thatare optimized for interfacing with ABTT terminus 10. In an exemplaryembodiment, device 52 is configured with a device width 58 and a devicelength 60, each of which is less than or equal to about 35 mm. In thisexemplary embodiment, drug container 54 includes a container width 62and a container length 64, each of which is less than or equal to 25 mm.However, in another exemplary embodiment, container width 62 and acontainer length 64 can each also be less than or equal to 10 mm, and inyet another exemplary embodiment, container width 62 and containerlength 64 can each be less than or equal to 7.5 mm. In yet anotherexemplary embodiment, device width 58 and device length 60 can each beless than or equal to 30 mm, and container width 62 and container length64 can each be less than or equal to 20 mm, less than or equal to 15 mm,less than or equal to 10 mm, or less than or equal to 7.5 mm. In afurther exemplary embodiment, device width 58 and device length 60 caneach be less than or equal to 20 mm, and container width 62 andcontainer length 64 can each be less than or equal to 10 mm, or lessthan or equal to 7.5 mm. In yet a further exemplary embodiment, devicewidth 58 and device length 60 can each be less than or equal to 10 mm,and container width 62 and container length 64 can each be less than orequal to 2.5 mm. The area outside the drug containing area is referredas edge or border 56, and the dimension of edge 56 is associated withthe strength of the adhesive. Therefore, an edge with a strong adhesivecan be made very small, such as equal to or less than 1 mm for example,and in this embodiment, the drug container 54 can have a container width62 or a container length 64 measuring in a range from 1 mm to 40 mm. Itshould be noted that the whole surface area, identified by device width58 and device length 60, can be covered by an adhesive surface, with thedrug disposed behind this surface, and in this embodiment the whole areacontains drug and there is not a separate edge with adhesive.

The larger container width 62 and container length 64 of drug container54 become, the easier it is to assure drug placement on ABTT terminus10. However, the larger container width 62 and container length 64become, the more uncontrolled delivery of drugs becomes. Accordingly,smaller container widths 62 and container lengths 64 are preferred forcontrolled, efficient delivery of drugs located in drug container 54 toABTT terminus 10.

The larger device width 58 and device length 60 of device 52 become, theeasier it is to handle and place device 52. However, device width 58 anddevice length 60 are practically determined by an adjacent eye of apatient or subject, since ABTT terminus 10 is very near to the eye, andmost patients or subjects object to the placement of objects on or overthe eye. Accordingly, a smaller device width 58 and device length 60 arepreferred for patient comfort, but the smaller device width 58 anddevice length 60 become, the more difficult it is to handle and placedevice 52.

As described herein, it should be understood that skin without fat ispresent under ABTT terminus 10, extending about 22 mm along the uppereyelid, and 6 to 7 mm along a line perpendicular to the eyelid, as shownin FIG. 2B, terminating at the superior edge of the eyebrow. A lowereyelid skin surface 17 with a minimal amount of fat is located along theedge of the lower eyelid, and extends about 10 mm from the edge of thelower eyelid, and is also a preferred area for administering drugstransdermally. While this area includes some fat, and does not include avein, the numerous capillaries in this area feed veins that flow intoABTT 12, such as angular vein 20.

FIG. 7 shows another passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 66. Device 66 is configured to include a shape that isadapted to fit to the curved anatomy of ABTT terminus that may bedescribed by many terms, including kidney, bean, banana, boomerang,comma, curvilinear, and arc. As with the configuration of FIGS. 4 and 6,a portion 68 of device 66 that is configured to interface with ABTTterminus 10 is configured with a convex curvilinear shape, on which ispositioned a drug patch or reservoir 70, shown exposed in FIG. 7.

FIG. 8 is a view of a general configuration of a transdermal deliverydevice in accordance with an exemplary embodiment of the presentdisclosure, indicated generally at 72. Device 72 includes a first, drugcontainer portion 74 is positioned along device 72. Device 72 includes ashape similar to device 66 shown in FIG. 7. In an exemplary embodiment,device 72 extends in an arc 76 of about 60 degrees, centered on drugcontainer portion 74. However, in another exemplary embodiment, device72 extends in a first arc 78 of at least 50 degrees from a center ofdrug container portion 74, and a second arc 80 of at least 50 degreesfrom a center of drug container portion 74. Device 72 further includes afirst end 82, which is configured to be positioned in a region between apatient's eye and eyebrow, and a second end 84, which is configured tobe positioned in a region between a patient's eye and a patient's nose.In an exemplary embodiment, first end 82 includes a first transversewidth 86 positioned a first longitudinal length 88 from first end 82along a centerline 90 of device 72, and first transverse width 86 is 15mm±8 mm, and first longitudinal length 88 is 7.5 mm±5 mm. Also in anexemplary embodiment, second end 84 includes a second transverse width92 positioned a second longitudinal length 94 from second end 84 alongcenterline 90, and second transverse width 92 is greater than or equalto first transverse width 86 and second longitudinal length 94 isapproximately equal to first longitudinal length 94. The effect of thesedimensions is that first end 82 is smaller in width than second end 84,giving device 72 a shape similar to an elongated and curved tear drop.

In another exemplary embodiment, device 72 can include a second end 96,shown in dashed lines in FIG. 8, and a third transverse width 98positioned a third longitudinal distance 100 from second end 96 alongcenterline 90, wherein third transverse width 98 is approximately equalto first transverse width 86 and third longitudinal distance 100 isapproximately equal to first longitudinal length 88. The effect of thisconfiguration is that device 72 attains a shape more similar to aboomerang than a teardrop.

One challenge with transdermal delivery devices is assuring sufficientadherence to the skin on and adjacent to ABTT terminus 10. One solutionis to provide sufficient area for adhesive on a device, such as device72, to adhere to a patient's skin. The exemplary configuration of device72 includes an elongated shape that extends along centerline 90 for atleast twice the diameter of drug container portion 74, in addition tothe diameter of drug container portion 74, for a total length alongcenterline 90 of at least three times the diameter of drug containerportion. It should also be understood that a strong adhesive allowsdecreasing the dimensions of the area surrounding the drug area, asdescribed herein.

One way to define an inner and outer dimension of a transdermal deliverydevice is by using two circles.

In an exemplary embodiment shown in FIG. 9, a first circle 102 includinga first center or origin 104 and a first diameter 106 is overlapped by asecond circle 108 including a second center or origin 110 and a seconddiameter 112. In an exemplary embodiment, first diameter 106 is greaterthan or equal to second diameter 112, with first diameter 106 being in arange 15 mm to 50 mm, and second diameter 112 being in a range 8 mm to50 mm. Second center or origin 110 is offset from first center or origin104 by an offset distance 114 that is determined by first diameter 106and second diameter 112, which determines a gap or width 116 between anexterior 118 of second circle 108 and an interior 120 of first circle102. The choices of first diameter 106, second diameter 112, and offsetdistance 114, along with a design position 122 for a transdermaldelivery device, is determined at least partially by a desired width ofa drug container or reservoir. In an exemplary embodiment, gap or width116 will be configured to provide a drug container or reservoir width ofat least 3 mm. In yet another exemplary embodiment, second diameter 112is approximately one half first diameter 106. It should be understoodthat the dimensions of the drug container or reservoir can have anydimension that fits between the eye and eyebrow and that includes theABTT terminus 10 or any of the veins 14, 16, 18, 20, and 22.

In another exemplary embodiment shown in FIG. 10, a second circle 130including a second center or origin 132 and a second diameter 134 ispositioned within a first circle 124 including a first center or origin126 and a first diameter 128. In an exemplary embodiment, first diameter128 is greater than or equal to second diameter 134, with first diameter128 being in a range 10 mm to 60 mm, and second diameter 134 being in arange 5 mm to 50 mm. Second center or origin 132 is offset from firstcenter or origin 126 by an offset distance 136 that is determined byfirst diameter 128 and second diameter 134, which determines a gap orwidth 138 between an exterior 140 of second circle 130 and an interior142 of first circle 124. The choices of first diameter 128, seconddiameter 134, and offset distance 136, along with a design position 144for a transdermal delivery device, is determined at least partially by adesired width of a drug container or reservoir. In an exemplaryembodiment, gap or width 138 will be configured to provide a drugcontainer or reservoir width of at least 3 mm. In yet another exemplaryembodiment, second diameter 134 is approximately one half first diameter128. A tear drop shape as previously described is included in thisembodiment. Preferably, the whole surface of the tear drop and boomerangembodiments of FIGS. 8-10 contain drug, and in these embodiments, thedrug surface includes an adhesive.

FIG. 11 is a view of a patient or subject's face 146 on which ispositioned a passive transdermal delivery device 148 configured inaccordance with an exemplary embodiment of the present disclosure.Transdermal drug delivery device 148 includes a drug delivery region 150that can be larger than ABTT terminus 10, but preferably needs to be ina region 152 bounded by eyebrow 154, nose 156, and eye 158, where ABTTterminus 10 is located. Drug delivery region or portion 150, thoughshown in phantom lines in FIG. 11 as a circular shape, can be othershapes, such as kidney, polygonal, etc., as long as region 150substantially overlaps ABTT terminus 10. In the context of thisdisclosure, substantially overlaps is preferably an overlap of ABTTterminus 10 by drug delivery region 150 of at least 80%, though anoverlap as low as 50% can still provide a therapeutically effective dosein some situations. The goal in every case should be a 100% overlap ofABTT terminus 10 by drug delivery region 150.

It should be understood that the drug delivery area does not need to beexactly overlying ABTT terminus 10, but can be located adjacent to ABTTterminus 10, since drug entering the skin in the region adjacent to ABTTterminus 10 will be carried towards ABTT terminus 10. The adjacent areasvary with the location on the face. As shown in FIG. 2B, a firstadjacent area 21 extends over a diameter of about 35 mm centered on ABTTterminus 10, excluding eye 31. A second adjacent area 23 extendssuperiorly about 25 mm from first adjacent area 21 along front vein 14.A third adjacent area 25 extends transversely or laterally about 25 mmfrom second adjacent area 23 along supraorbital vein 18. A fourthadjacent area 27 extends transversely or laterally about 30 mm fromfirst adjacent area 21. A fifth adjacent area 29 extends about 30 mmalong angular vein 20 from first adjacent area 21 and about 25 mm alonglower eyelid skin surface 17 from first adjacent area 21. It should beunderstood that while application of transdermal delivery devicesapplied in the aforementioned adjacent areas provide drug delivery toveins or capillaries that flow into ABTT 12, the further these areas arefrom ABTT terminus 10, the less effective drug application becomes.Accordingly, the smallest possible distance from ABTT terminus 10 ispreferred for drug delivery. Thus, while first adjacent area 21 can be35 mm in diameter, a smaller diameter centered on ABTT terminus 10 ispreferred, such as a diameter of about 30 mm, 25 mm, 20 mm, or less.

FIGS. 12 and 13 are views of a passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 160. Device 160 includes a device support 162that serves to provide structure and support for the various elements ofdevice 160. Device 160 further includes a drug container or reservoir164 positioned on device support 162 in a location that locates drugcontainer 164 over ABTT terminus 10 when device 160 is placed as shown,for example, in FIG. 11. Drug container 164 is covered prior to use by aremovable or peelable layer 166, which may also be described as arelease liner, which protects drug container 164 and protects peoplecoming into contact with device 160 from the drug in drug container 164.Removable layer 166 is adhered to device 160 by an adhesive layer 168positioned between device support 162 and removable layer 166. Removablelayer 166 can be configured to include a tab 170 that is without orabsent adhesive to enable a user to grasp a portion of removable layer166 more easily to separate removable layer 166 from device 160. Onceremovable layer 166 is separated from device 160, the drug located indrug container 164 is exposed and ready for application to ABTT terminus10 for transdermal delivery through ABTT terminus 10 to ABTT 12.

While drug container 164 is shown as a bubble or unified structure, itshould be understood that a deliverable drug may also be infused oravailable in adhesive layer 168. Further, in the exemplary embodiment ofFIG. 13, the drug located in drug container 164 may be activated by aseparate chemical once removable layer 166 is separated from device 160.For example, alcohol, water, a liquid permeability enhancer, or anotheractivation compound may be applied to the drug in drug container 164prior to placement of device 160 on a patient or subject.

FIGS. 14 and 15 are views of another passive transdermal delivery devicein accordance with an exemplary embodiment of the present disclosure,indicated generally at 172. Device 172 includes features that may besimilar to device 160, including a support 174 that can be similar todevice support 162, a drug container or reservoir 176 positioned ondevice support 174 in a location that locates drug container 176 overABTT terminus 10 when device 172 is placed as shown, for example, inFIG. 11. Drug container 176 is covered prior to use by a removable orpeelable layer 178 that protects drug container 176 and protects peoplecoming into contact with device 172 from the drug in drug container 176.Removable layer 178 is adhered to device 172 by an adhesive layer 168positioned between device support 174 and removable layer 178. Removablelayer 178 can be configured to include a tab 170 that is without orabsent adhesive to enable a user to grasp a portion of removable layer178 more easily to separate removable layer 178 from device 172. Onceremovable layer 178 is separated from device 172, the drug located indrug container 176 is exposed and ready for application to ABTT terminus10 for transdermal delivery through ABTT terminus 10 to ABTT 12.

Device 172 includes an absorbent layer 180 positioned between devicesupport 174 and drug container 176. The drug located in drug container176 may be activated by a separate chemical once removable layer 178 isseparated from device 172. For example, alcohol, water, a liquidpermeability enhancer, or another activation compound may be applied tothe drug in drug container 164 prior to placement of device 160 on apatient or subject. However, absorbent layer 180 is configured to absorbthe separate chemical and then to activate the drug by enhancingpermeation, such as, for example, by adding ethanol, including byliquefying the drug, or infusing the drug with a liquid to improvepermeability with skin. In the embodiment of FIG. 15, the drug may gothrough a phase change or soften from a portion of the drug that is awayfrom the skin of a patient, which provides a mechanism to control theinitial rate of drug flow into a patient that is different from theembodiment of FIG. 13.

FIGS. 16 and 17 are views of a passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 182. Device 182 includes a support 184 on whichis located a drug container or reservoir 186. When a removable orpeelable layer (not shown in this embodiment) is separated from device182, a drug 188 is accessible from an exterior of device 182 and is ableto flow through ABTT terminus 10 when device 182 is positioned such thatdrug container 186 is positioned on, over, or adjacent to ABTT terminus10.

FIG. 18 is a view of another passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 190. Device 190 includes a first drug containeror reservoir 192 and a second drug container or reservoir 194 positionedon a support 196. First drug container 192 is positioned on a firstportion 198 of device support 196, and when device 190 is positioned ona patient or subject's face, first drug container 192 is configured tobe positioned at least on ABTT terminus 10, and can extend to cover aportion of superior palpebral vein 16. In an exemplary embodiment, afirst portion length 200 of first portion 198 is equal to or less than30 mm. In another exemplary embodiment, first portion length 200 isequal to or less than 20 mm. In a further exemplary embodiment, firstportion length 200 is equal to or less than 15 mm. In yet anotherexemplary embodiment, first portion length 200 is equal to or less than5 mm. Second drug container 194 is positioned on a second portion 202 ofdevice support 196, and when device 190 is positioned on a patient orsubject's face, second drug container 194 is configured to be positionedto extend along a portion of angular vein 20. In an exemplaryembodiment, second portion length 204 is greater than or equal to 5 mm.In another exemplary embodiment, second portion length 204 is greaterthan or equal to 15 mm. In yet another exemplary embodiment, secondportion length 204 is greater than or equal to 25 mm. In a furtherexemplary embodiment, second portion length 204 is greater than or equalto 40 mm. Device 190 also includes a removable or peelable portion thathas been removed to better show certain features of FIG. 18. While drugdelivery to ABTT terminus 10 is preferred due to the lack of fat underABTT terminus 10, in some situations the amount of drug needed is suchthat more transdermal drug flow is required than ABTT terminus 10 alonecan provide. In such situations, including any device of the presentdisclosure that overlies de area of any of the veins 14, 16, 18, 20, and22 may augment the effect and the amount of drug delivered to the brainvia ABTT 12.

FIG. 19 is a view of a passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 206. Device 206 includes a support 208, and support 208includes a first drug container or reservoir 210, a second drugcontainer or reservoir 212, and a third drug container or reservoir 214,positioned thereon. Second drug container 212 includes an ABTT interfaceportion 216 and an angular vein interface portion 218. When device 206is positioned on a subject or patient's face such that ABTT interfaceportion 216 is located on the subject or patient's ABTT terminus 10,angular vein interface portion 218 extends along the subject orpatient's angular vein 20. First drug container 210 is positioned ondevice support 208 such that first drug container 210 is located on,over, or adjacent to at least a portion of superior palpebral vein 16when device 206 is positioned on a patient or subject's face in anorientation such as that shown in FIG. 11. Third drug container 214 ispositioned on device support 208 such that third drug container 214 islocated on, over, or adjacent to at least a portion of angular vein 20when device 206 is positioned on a patient or subject's face in anorientation such as that shown in FIG. 11.

FIG. 20 is a view of a transdermal delivery device in accordance with anexemplary embodiment of the present disclosure, indicated generally at220. The transdermal delivery devices disclosed herein can be achallenge to properly place for some individuals, and for thoseinexperienced in positioning devices on ABTT terminus 10, given its sizeand location. To assist in placement of the various devices disclosedherein, a notch or indicator 222 may be located to align device 220 witha facial feature, such as a corner 224 of an eye 226.

FIG. 21 is a view of another passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 228. Device 228 includes a support 230 thatextends from a region 232 between an eye 234 and an eyebrow 236, overABTT terminus 10, and then alongside a nose 238. Positioned on devicesupport 230 is a plurality of drug containers or reservoirs 240 a-e thatmay be configured as round, elliptical, or elongated, as shown herein,or may be square or rectangular, as shown in FIG. 21. Device 228 canalso include an alignment aid, such as an indicator 242 or notch 243. Inthe exemplary embodiment of FIG. 21, drug container 240 a configured tobe positioned on, over, or adjacent ABTT terminus 10 when device 228 isproperly positioned on a patient or subject's face 244. Drug containers240 b-e are configured to be positioned on, over, or adjacent angularvein 20 when device 228 is properly positioned on face 244, to augmentthe flow of drugs into ABTT 12. Alternatively, a thermoelectric devicecan be included with each drug container 240 a-e, making device 228 anactive device.

FIG. 22 is a perspective view of a passive transdermal delivery devicein accordance with an exemplary embodiment of the present disclosure,indicated generally at 246. Device 246 includes a first, drug deliveryside 248, and a second, support side 250. Device 246 further includes aremovable or peelable portion that has been removed to show drugdelivery side 248. In the embodiment of FIG. 22, drugs are configured toextend over most or all of first, drug delivery side 248. Theconfiguration of device 246 increases the likelihood of placement ofdevice 246 over ABTT terminus 10, though some drugs may permeate areasof a patient or subject's face that are less effective than ABTTterminus 10. FIG. 23 is a view of device 246 positioned on a patient orsubject face 252.

FIG. 24 is a side view of a patient's face on which are positioned aplurality of passive transdermal delivery devices in accordance with anexemplary embodiment of the present disclosure. A first transdermaldelivery device 254, which may be similar or identical to any of thetransdermal delivery devices configured to be positioned on ABTTterminus 10, shown in phantom lines in FIG. 24, and compatible with theother transdermal delivery devices associated with this embodiment, isconfigured to be positioned to deliver drugs to ABTT terminus 10, atleast a portion of superior palpebral vein 16, shown in phantom lines inFIG. 24, and at least a portion of angular vein 20, also shown inphantom lines in FIG. 24. A second transdermal delivery device 256 ispositioned on the skin along and over at least a portion of frontal vein14 and/or supraorbital vein 18, shown in phantom lines in FIG. 24. Athird transdermal delivery device 258 is positioned along and over atleast a portion of angular vein 20. As has been described herein,frontal vein 14, superior palpebral vein 16, and angular vein 20 allfeed into ABTT 12, shown in phantom in FIG. 24, and then into the coreof the human brain. While ABTT terminus 10 provides a unique locationfor transdermal delivery of drugs given the lack of fat, and the minimalthickness of the skin in this location, the amount of drugs needed maybe such that transdermal delivery to ABTT terminus 10 only isinsufficient for a therapeutically effective dosage, in the event that alarge amount of drugs need to be administered or when there is a needfor extended period for drug release. Accordingly, additional drugs canbe delivered to ABTT 12 by way of veins 14, 16, 18, and 20/22, all ofwhich make use of the direct connection of these veins to ABTT 12 andthe core of the brain. In these embodiments, the drug delivery devicemay lie adjacent to the nose when overlying angular vein 20, below thenose when overlying facial vein 22, between the eyebrow and on theforehead when overlying the frontal vein 14, along the inferior edge ofthe eyebrow, in the region of the upper eyelid, when overlying thesuperior palpebral vein 16, and along the superior edge of the eyebrowon the forehead region when overlying the supraorbital vein 18. Theadditional drug delivery devices provide an increased quantity of drugs,and because the permeation rate is lower through the skin over veins 14,16, 18, and 20/22, the drugs in devices in those locations provide drugsfor a longer period.

FIG. 25 is a view of a patient or subject's face 260 with a passivetransdermal delivery device in accordance with an exemplary embodimentof the present disclosure positioned thereon, indicated generally at262. Device 262 is configured as a triangular shape, and is configuredto include a drug delivery region or portion 264 that extends oversubstantially the entire surface of device 262. In the context of thisembodiment, substantially is at least 90% of the surface of device 262.Though an arc, banana, bean, etc., shape, such as that shown in FIG. 23,provides a relatively good match with the unique geometry of the facearound ABTT terminus 10, other shapes can also provide an acceptablematch with this geometry, such as a triangle. The triangular shape ofdevice 262 is configured to extend into a first region 266 between aneyebrow 268 and an eye 270, and into a second region 272 between a nose274 and eye 270.

FIG. 26 is a view of face 260 with another passive transdermal deliverydevice in accordance with an exemplary embodiment of the presentdisclosure positioned thereon, indicated generally at 276. Device 276 istriangular, similar to device 262, and is positioned generally in thesame location as device 262. However, device 276 is configured toinclude a drug delivery container, reservoir, or region 278 that isconfigured to be positioned on, over, or adjacent to ABTT terminus 10when device 276 is properly positioned on face 260. Additionally, drugdelivery container 278 is sized and dimensioned to be the approximatesize of ABTT terminus 10. Device 276 is further configured to include anotch or indicator 280 to assist with the positioning of device 276.

FIG. 27 is a view of face 260 with yet another passive transdermaldelivery device in accordance with an exemplary embodiment of thepresent disclosure positioned thereon, indicated generally at 282.Device 282 is configured with a triangular portion 284 on the portionsof device 282 that extend along eyebrow 268 and nose 274, and an arcedportion 286 on the portions of device 282 that extend along eye 270.Thus, exemplary transdermal delivery devices may combine the geometry ofmore than one embodiment disclosed herein effectively to take advantageof the various disclosed embodiments. Device 282 further includes a drugcontainer, reservoir, or delivery portion 288 that extends oversubstantially an entire side of device 282 that interfaces with the skinof face 260 in an area around ABTT terminus 10.

FIG. 28 is a view of a patient or subject's face 290 with a furtherpassive transdermal delivery device in accordance with an exemplaryembodiment of the present disclosure positioned thereon, indicatedgenerally at 292. Device 292 includes a drug container or reservoir 294configured to be positioned on ABTT terminus 10. Device 292 includes ashape that can be described as elongated or elliptical, with drugcontainer 294 positioned closer to a first end 296 of device 292 than asecond end 298 of device 292. Device 292 extends downwardly on face 290alongside a nose 300 in a region 302 between nose 300 and an eye 304.

FIG. 29 is a view of face 290 with a still further transdermal deliverydevice in accordance with an exemplary embodiment of the presentdisclosure positioned thereon, indicated generally at 306. Device 306 isconfigured to extend along a region 308 located between eye 304 and aneyebrow 310. Device 306 includes a first portion 312 that isapproximately rectangular in shape and a second portion 314 thatincludes a triangular shape configured to extend into a corner region316 bounded by eyebrow 310, nose 300, and eye 304. Device 306 includes afirst drug container 318, a second drug container 320, and a third drugcontainer 322, all of which are shown with hidden lines, extending alongthe longitudinal length of device 306. First drug container 318 isconfigured to be positioned on ABTT terminus 10. Second drug container320 and third drug container 322 are configured to be positioned on aportion of superior palpebral vein 16 when device 306 is located on face290. Device 306 may include a single removable or peelable portion, orit may include a plurality of removable portions, with at least oneportion associated with at least one drug container. The benefit of sucha configuration is that it permits significant variation in drug dosesto be applied to the face for delivery into ABTT 12.

FIG. 30 is a plan view of a passive transdermal delivery deviceconfigured to simultaneously delivery two different drugs, in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 324. Device 324 is configured with a first drug deliverycontainer 326 and a second drug delivery container 328, both of whichare configured to be positioned over ABTT terminus 10 at the same time.When a removable strip (not shown) is separate from device 324, thedrugs in first container 326 and second container 328 are available tobe positioned in contact with the skin of a patient or subject. Firstcontainer 326 and second container 328 can be identical in size with adifferent skin permeability, effectively modifying the ratio of drugsdelivered to a patient or subject's ABTT 12. First container 326 andsecond container 328 can be configured to have different cross-sectionalareas, as shown in FIG. 30, with approximately the same skinpermeability, which then delivers two different quantities of the drugsin first container 326 and second container 328 through the skin of apatient into ABTT 12. It should be understood that by selecting acombination of cross-sectional areas and skin permeability, an infinitenumber of ratios of drug delivery can be configured for delivery throughthe skin of ABTT terminus 10. A configuration such as that of device 324is beneficial for delivery of at least two drugs simultaneously, whichis desirable for certain medical conditions. It should be understoodthat one container may have a permeation enhancer and a second containermay have a drug, the permeation enhancer being released first by virtueof permeability of a membrane holding the permeation enhancer, followedby the drug release.

FIGS. 31-33 are views of a passive transdermal delivery device withextended drug delivery capability in accordance with an exemplaryembodiment of the present disclosure, indicated generally at 330. Device330 includes a support 332 on which is positioned a spacer layer 334that is configured with cutouts to define a first volume 336, located ina first portion 337, and a second volume 338 located in a second portion339. First portion 337 is connected to second portion 339 by connectionportion 341. A cover layer 340 is positioned over spacer layer 334 andis configured to cover second volume 338 while leaving first volume 336open. A removable or peelable layer 342 is configured to cover andprotect first volume 336, along with an adhesive layer 344 positionedbetween removable layer 342 and cover layer 340. Removable layer 342 mayinclude a tab 346 that extends beyond device 330 to enable grasping ofremovable layer 342 to remove layer 342. An absorbent material 348 ispositioned in first volume 336 that readily absorbs a drug fortransdermal delivery. A drug 350 is located in second volume 338, whichserves as a feeder reservoir to absorbent material 348 in first volume336. Drug 350 may be inserted or enter through an opening 352 formed inspacer layer 334, and opening 352 can then be closed by a plug 354.Device 330 can be configured to include a flow control membrane 356positioned between feeder reservoir 338 and absorbent material 348. Flowcontrol membrane 356 moderates the rate of flow from feeder reservoir338 to absorbent material 348. Absorbent material 348 can be configuredto include a protruding portion 358 that extends beyond an outer plane360 of adhesive layer 344. Protruding portion 358 assures contact withthe skin of ABTT terminus 10 when removable layer 342 is separated fromdevice 330.

Device 330 is configured to provide an extended duration of drugdelivery to ABTT terminus 10. Such extended duration is provided byfeeder reservoir 338, and the rate of delivery to absorbent material348, which can be moderated or modified by flow control membrane 356.The flow from feeder reservoir 338 to absorbent material 348 is possiblebecause feeder reservoir 338 is configured to be positioned at alocation on a patient higher than absorbent material 348, such as aforehead of a patient, as shown in FIG. 33. Reservoir 338 feeds liquiddrug 350, by gravity, into first volume 336 positioned over ABTTterminus 10, where drug 350 permeates absorbent material 348 until drug350 reaches ABTT terminus 10.

While most of the drug delivery devices described to this point areconsidered passive delivery devices, even a passive delivery device canbe configured to include enhanced delivery features. One such passivetransdermal delivery device is shown in FIG. 34 and indicated generallyat 362. Device 362 includes a first layer 364, an adjacent second layer366, and another adjacent third layer 368, which define an internalvolume 370. Internal volume 370 is enclosed by a removable layer 372 atone end, and a cover layer 374 at a second end opposite the first end.

An absorbent material 376 containing a skin-permeable drug is positionedadjacent to removable layer 372 and is exposed when removable layer 372is separated from device 362. A flexible, impermeable membrane 378separates absorbent material 376 from the portion of internal volume 370that is adjacent the second end of internal volume 370. Flexible,impermeable membrane 378 is attached to at least one of first layer 364and second layer 366 or is captured between first layer 364 and secondlayer 366, which can then be secured to each other by an adhesive orother fastening apparatus. A slide plate 380 is positioned in a slot 382formed in at least one layer, or formed between, for example, secondlayer 366 and third layer 368, which then divides internal volume 370into a lower volume 384, which is configured to contain absorbentmaterial 376, and an upper volume 386.

A spring 390 and a pressure plate 388 are positioned in upper volume386, exerting force on slide plate 380. When slide plate 380 is pulledfrom device 362, the force of spring 390 causes pressure plate 388 tomove toward flexible impermeable membrane 378, placing pressure onmembrane 378 and, consequently, absorbent material 376. The pressureplaced on absorbent material 376 forces the drug in absorbent material376 to move outwardly, toward the skin of ABTT terminus 10 when device362 is properly positioned to locate absorbent material 376 on, over, oradjacent the skin of ABTT terminus 10. It should be understood thatother fastening apparatuses, devices, or mechanisms can be used toposition device 362 on the skin of ABTT terminus 10, such as an annularstructure, a structure connected to a frame, and the like, whichpositions and presses absorbent material 376 against the skin, and inthose embodiments there is no need for an adhesive surface area.

FIGS. 35 and 36 are views of another passive transdermal delivery devicein accordance with an exemplary embodiment of the present disclosure,indicated generally at 392. Device 392 is configured to include a shapethat matches the recess of a human eye socket 394. A drug container orreservoir 396 is oriented such that when device 392 is positioned in eyesocket 394, drug container 396 is in contact with ABBT terminus 10.Device 392 can be secured by a plurality of adhesive strips 398positioned on device 392 and configured to be secured to the skin of aface 400. In an exemplary embodiment, drug container 396 is oriented ata first angle 402 extending from a vertically extending axis 404, and ata second angle 406 extending from a horizontally extending axis 408 thatis approximately perpendicular to face 400. In an exemplary embodiment,first angle 402 is in the range of 20 to 75 degrees, and second angle406 is in the range of 10 to 50 degrees. Adhesive tabs may havedissimilar dimensions, to secure device 392 to the skin, based on theamount of space, which is more limited in the upper portion in contrastto the nose and cheek area.

FIG. 37 is a view of a support device for transdermal delivery device392, indicated generally at 410. Support device 410 is configured toposition at least one device 392 on a patient by positioning device 392in a socket 412. Each socket 412 is configured in a flexible plate 414that provides sufficient rigidity to maintain drug container 396 ofdevice 392 in contact with ABTT terminus 10. A stretchable or adjustablestrap 416 is configured to secure flexible plate 414 on a patient'sforehead, also providing the force needed to maintain drug container 396in contact with ABTT terminus 10.

FIGS. 38 and 39 are views of a support apparatus and passive transdermaldelivery device in accordance with an exemplary embodiment of thepresent disclosure, indicated at 418 and 420, respectively. Supportapparatus 410 includes one or more straps 422 for securing supportapparatus 410 to a subject or patient's head. Straps 422 can beconfigured to be flexible or adjustable. Support apparatus 410 furtherincludes a flexible plate 424 configured to support avertically-extending support arm 426. One or more angled braces 428 canconnect vertically-extending support arm 426 to plate 424 to providerigidity to support arm 426. Flexible plate 424 is configured to includea pocket 430 formed by a clear sheet 432. A sheet 434 including a labelfor a drug being applied by delivery device 420 can be inserted intopocket 430 for view by an external observer, such as a doctor, nurse,paramedic, technician, and the like. Support arm 426 includes an angledsupport pad 438 containing a pocket 440. Transdermal delivery device 420includes a securing mechanism 442 provided on device 420 to attachdevice 420 to a mating feature 444 in angled support pad 438. Oncedevice 420 is secured to support apparatus 418, a removable layer can beseparated from support apparatus 418 to expose a drug container orreservoir 446, after which support apparatus 418 can be secured to ahead such that drug container 446 is positioned against ABTT terminus10.

FIG. 40 is a view of another passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 448. Device 448 includes a support 450 and astrap 452 configured to secure device support 450 to a patient orsubject's head. Support 450 is further configured to include a pluralityof openings 454 that permits the patient or subject to see while wearingdevice support 450. Device support 450 includes a first drug container456 and a second drug container 458 configured to be oriented similar tothe embodiment of FIGS. 35-37 to position first drug container 456 andsecond drug container 458 in contact with a patient or subject's ABTTterminuses 10. Device support 450 further includes a third drugcontainer 460 and a fourth drug container 462 positioned on an extensionplate 464 to extend vertically above first drug container 456 and seconddrug container 458. Third drug container 460 and fourth drug container462 are positioned to be in contact with at least a portion of frontalveins 14 or supraorbital veins 18. Device support 450 yet furtherincludes a fifth drug container 466 and a sixth drug container 468positioned on a first angular extension 470 and a second angularextension 472, respectively. Fifth drug container 466 and sixth drugcontainer 468 are configured to contact at least a portion of angularveins 20 and may extend to contact at least a portion of facial veins 22in the cheek.

FIG. 41 is a view of another passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 474. Transdermal delivery device 474 is shownpositioned on ABTT terminus 10. Device 474 includes a support 476 and adrug container or reservoir 478. Device 474 further includes an adhesivelayer 480 that is configured to generate heat when a removable layer isseparated from device 474. The benefit of heat generation in device 474is that heat improves the permeability of skin 482 to the drug in drugcontainer 478. FIG. 41 also shows the lack of fat and the thinnest skinin the body at ABTT terminus 10, and fat with thick skin 484 located inareas outside ABTT terminus 10. As has been explained herein, drugs thatflow through the skin of ABTT terminus 10 flow into ABTT 10, and theninto cavernous sinus 486. From cavernous sinus 486, drugs flow directlyinto the surrounding tissues of a brain 488, without the complexities offlowing through the digestive system and the circulatory system,including the liver and the kidneys. Accordingly, drugs that flowdirectly into ABTT 12 from all sources, especially ABTT terminus 10 andveins 14, 16, 18, 20, and 22, provide a greater effect on brain tissuesthan any other application of drugs to the human body, and consequently,fewer amounts of drugs and/or lower drug concentration than what is usedin conventional patches, as described herein, need to be applied atthese locations to be effective.

FIG. 42 shows yet another passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 490. Device 490 includes a pair of glasses 492with a first or left side frame 494, and a second or right side frame496, which are configured to connect to each other by way of a removableand exchangeable nose piece 498. Removable nose piece 498 is configuredto include projections 500 and 502 in the right and left siderespectively. Each project 500 and 502 includes a drug container 504configured to be positioned at angles similar to the angles describedfor the embodiment of FIG. 36, thus configured to be in a location thatplaces each drug container 504 in contact with ABTT terminus 10.Removable nose piece 498 is configured to connect left frame 494 toright frame 496, and to support left frame 494 and right frame 496 as anassembly, pair of glasses 492. Removable nose piece 498 further includesat least one attachment or fastening feature 506 on each side ofremovable nose piece 498 configured to mate with complementaryattachment or fastening features 508 located in left frame 494 and rightframe 496.

FIG. 43 is a view of a passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure, indicated at510. Device 510 includes a first drug container or reservoir (not shown)positioned on a first pad 512 and a second drug container or reservoir(not shown) positioned on a second pad 514, with each drug containerconfigured to be positioned over a respective ABTT terminus 10 whendevice 510 is properly positioned on a face. Each pad 512 and 514 can beconfigured similar to, for example, the embodiments of FIGS. 12, 16, and18. Device 510 further includes a nose clip 516 configured to besupported on a nose 518. The frictional contact of nose clip 516 withnose 518 provides sufficient support for device 510 to maintain contactbetween first pad 512 and second pad 514 with a respective ABTT terminus10.

FIG. 44 is a view of another passive transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 520. Device 520 includes a first drug containeror reservoir (not shown) positioned on a first pad 522 and a second drugcontainer or reservoir (not shown) positioned on a second pad 524, witheach drug container configured to be positioned over a respective ABTTterminus 10 when device 520 is properly positioned on a face. Each pad522 and 524 can be configured similar to, for example, the embodimentsof FIGS. 12, 16, and 18. Device 520 further includes a pair of nose pads526 configured to be supported on nose 518. The frictional contact ofnose pads 526 with nose 518 provides sufficient support for device 520to maintain contact between first pad 512 and second pad 514 with arespective ABTT terminus 10. First pad 522, second pad 524, and nosepads 526 are positioned on a frame support 528, such that the grip ofnose pads 526 is configured to support first pad 522 and second pad 524.It should be understood that a clip-like mechanism and spring-likemechanisms can be present to further secure device 520 to the nose.

FIGS. 45 and 46 are views of a transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 530. Device 530 includes a first drug container 531positioned on a first pad 532 and a second drug container 533 positionedon a second pad 534. Device 530 also includes a first thermoelectricdevice 543 positioned in a central portion of first drug container 531and a second thermoelectric device 545 positioned in a central portionof second drug container 533. Thus, first drug container 531 and seconddrug container 533 are configured as annuluses, each with a centeropening in which is positioned a thermoelectric device. Device 530 isconfigured with a handle 536, and a pair of flexible arms 538 configuredto support first pad 532 and second pad 534. Handle 536 is configured tobe held by a subject or patient, or may be held by another person. In anexemplary embodiment, handle 536 is of a material sufficient rigid tosecure first pad 532 and second pad 534 against at least one ABTTterminus 10. Device 530 further includes a controller 535 for operatingdevice 530, a transmitter 537 for communicating with a remote electronicdevice 539, such as a cell phone, and a power supply 541, all of whichare located in handle 536.

FIG. 47 is a view of a passive transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 540. Device 540 includes a reservoir 542 located at the endof a flexible arm 544. Reservoir 542 is configured to include aninterior chamber 548, which is closed at one end by an absorbentmaterial 546. A liquid drug 550 is positioned within interior chamberprior to the installation of absorbent material 546. Absorbent material546 is protected by a drug impermeable and removable layer 552 that isseparated from device 540 prior to use. In the exemplary embodiment ofFIG. 47, device 540 is configured to be used on a patient or subjectsitting or standing upright. To be configured for such an orientation,device 540 is positioned at an angle 554 to a vertical axis 556. In anexemplary embodiment, angle 554 is in the range 20 degrees to 75degrees, which permits liquid drug 550 to contact absorbent material 546for transport to the skin of ABTT terminus 10.

FIG. 48 is a schematic view of a transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 558. Device 558 includes an absorbent material560 positioned on a pad 562 and connected by a fluid passage to aseparate reservoir 564. Device 558 is configured to position absorbentmaterial 560 on, over, or adjacent to the skin of ABTT terminus 10 whenpad 562 is positioned on a subject or patient's face. Device 558 isconfigured to provide a drug located in reservoir 564 to ABTT terminus10 for an extended period rather than being limited to the amount ofdrug that can be locally stored on a pad 562. Though not shown in FIG.48, device 558 can be configured to include one or more elements to beconsidered an active device, such as a thermoelectric device.

FIG. 49 is a schematic view of a transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 568. Device 568 includes an absorbent material570 located in a holder 572 and configured to be positioned on an ABTTterminus 10. Absorbent material 570 is connected by fluid passage 566 toseparate reservoir 564 and, similar to the embodiment of FIG. 48,reservoir 564 provides additional time for drugs to be delivered viaabsorbent material 570 to ABTT terminus 10. Though not shown in FIG. 49,device 568 can be configured to include one or more elements to beconsidered an active device, such as a thermoelectric device.

FIG. 50 is a schematic view of a transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 574. Device 574 includes a first pad 576, shownschematically, and a second pad 578, also shown schematically, supportedon a nose clip 580. Each of first pad 576 and second pad 578 areconnected by fluid passage 566 to reservoir 564. The embodiment of FIG.50 may include one or two reservoirs 564 to permit the delivery of drugsfor a longer period or for the delivery of two different drugs. Thoughnot shown in FIG. 50, device 574 can be configured to include one ormore elements to be considered an active device, such as athermoelectric device.

FIG. 51 is a schematic view of a transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 582. Device 582 includes a first pad 584configured to be positioned on ABTT terminus 10, a second pad 586configured to be positioned on a vein, such as frontal vein 14, and athird pad 588 configured to be positioned on another vein, such asangular vein 20. Each of first pad 584, second pad, 586, and third pad588 are connected to each other and supported by a frame 590. Though notshown in FIG. 51, device 582 can be configured to include one or moreelements to be considered an active device, such as a thermoelectricdevice.

FIG. 52 is a transdermal delivery system in accordance with an exemplaryembodiment, indicated generally at 592. System 592 includes at least onepassive or active transdermal delivery device 594 that may be any of thepassive transdermal delivery devices described herein, and a pair ofwarming and cooling gloves 596. Gloves 596 are connected to a controller598, which can be configured to include an ON/OFF switch 600, atemperature controller 602, and a temperature display 604. System 592provides an enhanced delivery of drugs to a subject or patient 606 bytricking the brain into functioning in a certain way. More specifically,system 592 operates by making the brain think that the ambienttemperature is about to become hot by activating thermal receptors inthe subject's hands by applying heat to gloves 596. The brain, sensingthe heat in the hands, prepares for the apparent increase in temperatureby causing cool blood to flow from one or more veins 14, 16, 18, or 20into ABTT 12. This blood flow will cause drugs flowing through ABTTterminus 10 and any drugs flowing through veins 14, 16, 18, or 20 toflow into ABTT 12 at a faster rate than might normally occur in typicalambient and body temperatures. Indeed, the brain may be causing warmblood to flow outwardly through ABTT 12, which would render theapplication of drugs less effective. Gloves 596 are also capable ofcooling the hands. If the face contains warm blood, the brain can stillcause inward blood flow, accomplishing the same effect. In order to knowhow the brain is functioning with respect to facial blood flow, system592 may be configured to include a plurality of temperature sensorspositioned to measure ambient temperature, facial skin temperature, andtemperature at an ABTT 10, which can be presented on temperature display604, as well as devices that measure blood flow.

FIG. 53 is a view of an active transdermal delivery system in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 610. System 610 includes an active transdermal deliverydevice 612, one or more electric gloves 614, one or more electric boots616, and a controller 618. Generally, device 612 is controllable toprovide flow of a drug to a patient or subject while gloves 614 andboots 616 are heated or cooled to fool the brain into controlling bloodflow from the face into ABTT 12. System 610 further includes a pluralityof temperature sensors, such as temperature sensor 608 for measuringambient temperature, and temperature sensors integral to gloves 614 andboots 616. Additional temperature sensor can be positioned to measureface and ABTT terminus temperature (not shown).

Device 612 includes a drug delivery interface 620 configured to delivera drug to ABTT terminus 10. Drug delivery interface 620 is connected bya fluid delivery system 622 to a reservoir 624. Fluid delivery system622 includes a variable or adjustable valve 626 and can include a pump628. When commanded by controller 618, variable valve 626 can be openedto permit a drug to flow from reservoir 624 through fluid deliverysystem 622 to drug delivery interface 620. If needed to augment drugflow, controller 618 may also command a pump to move the drug throughfluid delivery system 622 to drug delivery interface 620. Controller 618can be configured to include a display 630 to provide a readout oftemperature and other information, a temperature controller 632, a flowcontrol 634, and an ON/OFF switch 636, along with other controls. Asnoted with the embodiment of FIG. 52, the brain may be tricked byheating or cooling thermal receptors in the hands or feet by heating ofcooling gloves 614 and boots 616. The brain then causes blood flow, orincreased blood flow, from the veins of the face into ABTT 12 inresponse to the thermal stimulation of the hands and feet, improving andcontrolling the delivery of drugs to the brain. It should be noted thatexcessive drug flow can also be controlled by reducing the blood flow tothe brain by appropriate adjustment of glove 614 and boot 616temperature.

FIG. 54 is a view of another active transdermal delivery system inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 638. System 638 includes a drug deliveryinterface 640 configured to include a permeable material 642. Drugdelivery interface 640 is connected to a fluid reservoir 644 containinga drug 646. Interface 640 is connected to reservoir 644 by a fluiddelivery system that can include one or more fluid passages 650 and avariable valve 652. Reservoir 644 is configured to be pressurized by anair delivery system 654 that can include an air supply valve 656positioned between an air source 658 and fluid delivery system 648. Whena drug needs to be delivered to drug delivery interface 640, variablevalve 652 can be opened to start the flow of drug 646 from reservoir 644into fluid delivery system 648, and then to drug delivery interface 640.If the flow of drug 646 to drug delivery interface 640 is inadequate,air supply valve 656 is opened to connect air source 658 to reservoir644, forcing additional flow of drug 646 into fluid delivery system 648to drug delivery interface 640. Air source 658 can be any of a pluralityof sources of pressurized air, including nitrogen systems, filtered airpumps, and bottled air. In the embodiment of FIG. 54, air source 658 isconfigured as a balloon, which often is sufficient to provide enoughpressure to provide sufficient supply of drug 646 to drug deliveryinterface 640.

FIGS. 55 and 56 are views of an active transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 660. Device 660 includes a support 662 configuredto include a drug container or reservoir 664. Device 660 furtherincludes a removable or peelable layer 666 configured to protect drugcontainer 664 and an adhesive layer 668 positioned between removablelayer 666 and device support 662. Device 660 also includes athermoelectric device 670 positioned transversely between drug container664 and device support 662. When removable layer 668 is removed fromdevice 660, as shown in FIG. 55 (FIG. 56 shows removable layer 668 inplace), drug container 664 is exposed and ready for placement on ABTTterminus 10, secured by adhesive layer 668. Power is applied tothermoelectric device 670 through wires 672 to heat drug container 664and the skin around ABTT terminus 10. By heating drug container 664, thedrug contained therein becomes more energetic and more likely topermeate skin. Furthermore, the skin of ABTT terminus 10 also increasesin permeability due to the heat, and drug flow through ABTT terminus 10is thereby enhanced.

FIG. 57 is a view of a passive transdermal delivery module in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 674. Module 674 is configured to be attached to a pluralityof devices, such as glass frames, a head support, headband, hat, astandalone equipment support, etc. Module 674 includes a flexible arm676 that includes an attachment arrangement 678, which can be, forexample, a screw thread. A drug container or reservoir 680 is positionedon flexible arm 676 and is configured to contain a drug 682. Drug 682can be protected by a removable layer (not shown), until module 674 isready for use, at which time the removable layer is separated frommodule 674. Module 674 is beneficial for the flexibility that module 674provides given that it can be attached to a plurality of devices and isinfinitely adjustable to interface with ABTT terminus 10, and may notrequire an adhesive surface to maintain contact with a patient orsubject ABTT terminus 10.

FIG. 58 is a view of an active transdermal delivery module in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 684. Module 684 is shown attached to a glasses frame 686,which includes a power supply configured to provide power to athermoelectric device 688 positioned on module 684. Module 684 includesa flexible arm 690 that provides a route for wires 692 that providepower to thermoelectric device 688. Module 684 further includes a drugcontainer or reservoir 694 that stores a drug 696 and provides alocation to support thermoelectric device 688.

FIG. 59 is a view of another active transdermal delivery module inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 698. Module 698 includes a drug reservoir orcontainer 700 configured to include a liquid drug and an absorbentmaterial 702 to interface with ABTT terminus 10, and configured tosupport thermoelectric device 688. Module 698 further includes aflexible arm 704 configured to support drug reservoir 700. Flexible arm704 is configured to include an attachment feature (not shown) toconnect module 698 to one of a plurality of support devices. Flexiblearm 704 is configured to provide support for wires 706 that providepower to thermoelectric device 688 and a fluid passage 708 that connectsa separate drug reservoir to drug reservoir 700. As with otherembodiments incorporating a thermoelectric device, the device can affectthe flow of drugs into ABTT terminus 10.

FIG. 60 is a view of yet another active transdermal delivery module inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 710. Device 710 includes a support 712 thatprovides a location for thermoelectric device 688 and drug deliveryinterface 714. Drug delivery interface 714 provides a limited source ofdrugs since drug delivery interface 714 is not connected to a reservoir.Support 712 is connected to a flexible arm 716 that provides a locationfor wires 718 that deliver power to thermoelectric device 688. Module710 is useful for short term supply of a drug. Drug delivery interface714 is configured to be readily replaceable to replenish the supply ofdrugs to a patient or subject.

FIG. 61 is a view of a basic active transdermal delivery system inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 720. System 720 includes a drug deliveryinterface 722, a drug reservoir 724, and a controller 726. Drug deliveryinterface 722 includes an absorbent material 728 positioned in anannular thermoelectric device 730. Drug delivery device 722 is connectedto reservoir 724 by a flexible arm or support 732, which is configuredto support a fluid passage extending between reservoir 724 and absorbentmaterial 728. Controller 726 is connected to thermoelectric device 730by a wire or cable 734. Controller 726 is configured to connect anddisconnect power to thermoelectric device 730, and to vary the amount ofpower to control temperature delivered to a subject or patient. In anexemplary embodiment, controller 726 can also be configured to controlthe flow of a drug from reservoir 724 to drug delivery interface 722.Controller 726 can further include a display to present the temperatureof various locations, including ambient, facial skin, extremity (handsand feet), rectal, oral, axillary, ABTT terminus 10, and the like.

The goal of the flexible arm or support 732 is to permit adjusting theposition of drug delivery interface 722 to match the location of ABTTterminus 10 as well as possible, and to maintain contact betweenabsorbent material 728, or other drug delivery media, and ABTT terminus10. FIG. 62 is a view of a drug delivery interface incorporating aspring to assist in accordance with an exemplary embodiment of thepresent disclosure, indicated generally at 736. Drug delivery interfaceincludes a drug container or reservoir 738 positioned in an annularopening 740 of a thermoelectric device 742. Thermoelectric device 742and drug container are secured to a support base 744 by a plurality ofconnectors 746 that slidingly interface with a plurality of slots 748.In the exemplary embodiment of FIG. 62, slots 748 are located on supportbase 744, and connectors 746 are fixedly attached at a peripherallocation of thermoelectric device 742. A spring 750 is positionedbetween thermoelectric device 742 and support base 744. The function ofspring 750 is to permit drug delivery interface 736 to be moved intocontact with ABTT terminus 10, which then compresses spring 750, whichis configured to maintain contact with ABTT terminus 10 in the event oflimited movement of drug delivery interface 736. Drug delivery interface736 further includes a flexible arm or support 752, which furtherincludes an attachment arrangement 754 to permit secure attachment ofdrug delivery interface 736 to another device or apparatus, such as aseparate support. Flexible arm 752 further support wires 756 that routepower from a power supply or controller to thermoelectric device 742.

FIG. 63 is a view of an active transdermal delivery device configured todeliver two drugs, in accordance with an exemplary embodiment of thepresent disclosure, indicated generally at 758. It should be understoodthat FIG. 63 is configured as a block diagram, and certain features,such as drug containers, are positioned such that when device 758 isproperly placed on the skin, the appropriate features are positioned incontact with the skin. The thermoelectric devices described inconjunction with device 758 need not be positioned in direct contactwith the skin, but need to be positioned in a location that providesthermal communication with the skin.

Device 758 is configured to take advantage of change in skinpermeability with temperature, and, in some cases, the increasedtransport of drugs with temperature. For most drugs, as shown in studiesby Applicant, skin permeability increases with an increase intemperature, and decreases with a decrease in temperature. Accordingly,the flow of drugs through the skin may be halted by modifying skinpermeability with temperature. In addition, for drugs where skinpermeability increases with temperature, the mobility of the drugincreases with temperature, further improving the flow of drugs throughthe skin of ABTT terminus 10 to reach ABTT 12.

Device 758 includes a support 760, on which are positioned or located afirst drug container or reservoir 762 and a second drug container orreservoir 764, separated by a thermal insulator 766. Device 758 furtherincludes a first thermoelectric device 768 positioned on an oppositeside of first drug container 762 from second drug container 764, and asecond thermoelectric device 770 positioned on an opposite side ofsecond drug container 764 from first drug container 762. In theexemplary embodiment of FIG. 63, a power supply 772 is also positionedon support 760 and connected to various elements of device 758 toprovide power for operation. A first temperature sensor 774 and a secondtemperature sensor 776 are positioned in proximity to first drugcontainer 762 and second drug container 764, respectively. Firsttemperature sensor 774 and second temperature sensor 776 enable refinedcontrol of the temperature of first drug container 762 and second drugcontainer 764, and, consequently, control of the delivery of drugsthrough the skin. For example, by decreasing the temperature of firstthermoelectric device 768 by an amount equal to at least one degreeCelsius below the initial or nominal skin temperature, permeability ofthe skin to most drugs drops to approximately zero, effectively stoppingor shutting off the flow of drugs through the skin. Conversely,increasing the temperature of the skin a degree above the initial ornominal skin temperature increases skin permeability by about 30% formost of the drugs tested, and described herein. Thus, controlling thetemperature of a thermoelectric device positioned adjacent to a drugcontainer in contact with the skin controls drug flow through the skin.Thus, it is an object of the disclosure to provide a device thatcontrols flow of drugs through the skin using a combination of warmingand cooling.

Device 758 can further include a transmitter, receiver, or transceiver778 configured for communication with a separate electronic device 780,such as a cell phone, laptop, tablet, watch, etc. Such communicationwith separate electronic device 780 permits control of device 758 and,when device 758 is provided with sensors, monitoring of device 758.

FIG. 64 is a view of another active transdermal delivery deviceconfigured to deliver two drugs, in accordance with an exemplaryembodiment of the present disclosure and indicated generally at 782.Device 782 includes a support 784 on which is positioned a first drugcontainer or reservoir 786 and a second drug container or reservoir 788,separate by a thermal insulator 790. A first temperature sensor 792 maybe positioned proximate or over first drug container 786 and a secondtemperature sensor 794 may be positioned proximate or over second drugcontainer 788 to measure, indirectly, the temperature of the skin overwhich first drug container 786 and second drug container 788 arepositioned. Device 782 further includes at least one firstthermoelectric device 796, and may include a plurality of firstthermoelectric devices 796 positioned about a periphery of first drugcontainer 786, and at least one second thermoelectric device 798, andmay include a plurality of second thermoelectric devices 798 positionedabout a periphery of second drug container 788. First thermoelectricdevice(s) 796 and second thermoelectric device(s) 798 are positioned ona periphery that is away from the portion of the periphery that is alongthermal insulator 790. Device 782 is further configured to include apower supply 800 for providing power to the various elements positionedon device support 784. Device 782 further includes a controller 802configured to operate various elements of device 782, and a transceiver,transmitter, or receiver 804 configured to communicate with a separateelectronic device 806, which may be a cell phone, tablet, laptop, watch,etc.

FIG. 65 is a first graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure. Asdescribed herein, by controlling the temperature of the skin adjacent toan absorbent material, drug container, or drug reservoir, the flow of adrug through the skin can be controlled. FIG. 65 shows a stylized graphof drug flow from a conventional transdermal patch attached to the skinin comparison to one of the infinite patterns possible with an activelycontrolled transdermal device disclosed herein. A conventional devicebegins to deliver a drug to the skin at T0, building to a peak flow rateat T1. The drug then flows until drug depletion nears, at time T3,eventually falling to zero at time T4. In contrast, an activelycontrolled transdermal device generates transdermal drug delivery fasterthan a conventional device, shown by the steep slope at the beginning ofthe curve just after T0, which represents controlled fluid flow throughthe skin by increasing temperature with the thermal devices of thedisclosure. At time T2, the temperature of the skin is reduced todecrease drug flow until a new steady state is reached at time T3. Thedelivery rate is sustained from time T3 to time T4, at which time drugdelivery is reduced to zero, again by temperature control.

FIG. 66 is a second graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure. Fromtime T0 to T1, skin temperature is held below nominal, and a drugdelivery rate is minimal or zero. At time T1, skin temperature isincreased to raise the drug delivery rate rapidly to a peak at T2 toprovide an initial flood of drugs, followed by a decrease in skintemperature from time T2 to time T3, which reduces the flow of drugsthrough the skin. From time T3 onward, the flow rate of drugs throughthe skin is maintained at a steady state, sometimes supported by areservoir, which may be integral or separate.

FIG. 67 is a third graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure. InFIG. 67, the temperature is varied to turn drug flow off and on,increasing the rate of drug flow during each subsequent activation ofdrug flow.

FIG. 68 is a fourth graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure. InFIG. 68, the rate of drug flow is stepped up over time, until drug flowis turned off at time T8 by reducing skin temperature below nominal ornormal.

FIG. 69 is a fifth graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure. Therate of drug flow is opposite that shown in FIG. 68, beginning at arelatively high level and decreasing in steps over time until the drugflow is eventually reduced to zero by controlling the temperature of theskin.

FIG. 70 is a sixth graph demonstrating controlled drug flow inaccordance with an exemplary embodiment of the present disclosure. InFIG. 70, drug flow is turned on and off with time, with the maximum flowrate decreased each time.

FIGS. 72 and 73 are views of an active transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 810. Device 810 includes a frame 812 configuredto be supported on a person's ear and nose by an ear engagement portion814 and nose pads 816. Device 810 further includes a first drugcontainer 818 and a second drug container 820 configured to bepositioned on a patient or subject's ABTT terminuses 10 when device 810is positioned on an ear and a nose of a patient or subject's face.Device 810 further includes at least one first thermoelectric device 822and at least one second thermoelectric device 824 positioned to contactthe skin at or near ABTT terminus 10 when device 810 is positioned on asubject or patient's face. In the exemplary embodiment of FIG. 72,device 810 is configured to include a drug container or reservoir 826positioned on ear engagement portion in a location configured to contactretroauricular blood vessels located behind the ear. Device 810 isfurther configured to include a controller 828, a transceiver,transmitter, or receiver 830 configured to communicate with an externalelectronic device 832, and a power supply or supplies 834 configured toprovide power to the electronic elements of device 810.

FIG. 74 is a perspective view of an active transdermal delivery devicein accordance with an exemplary embodiment of the present disclosure,indicated generally at 836. Device 836 is configured to include aneyeglass frame 838 including lenses 840, temple pieces, 842, and nosepads 844. Device 836 is configured to include a first drug container orreservoir 846 and a second drug container or reservoir 848 configured tobe positionable such that first drug container 846 and second drugcontainer 848 will contact ABTT terminuses 10 of a patient or subjectwhen device 836 is positioned on the face of the patient or subject.Device 836 is further configured to include a plurality of electronicelements, such as a power supply 850, a controller 852, one or moretemperature sensors 854, and a transceiver, transmitter, or receiver 856configured to communicate with a separate electronic device 858. Device836 is configured to provide the benefits of conventional eyeglasseswith the benefits of the present disclosure to provide a multipurpose ormultifunction device for vision correction and transdermal drugdelivery.

FIG. 75 is a perspective view of an active transdermal delivery devicein accordance with an exemplary embodiment of the present disclosure,indicated generally at 860. Device 860 is configured as a pair ofeyeglasses, including a frame 862, lenses 864, and temple pieces 866.Device 860 further includes a separable nose piece 868 configured toattach to frame 862, and to communicate with electronic elementspositioned on frame 862 by way of a connector 870. Nose piece 868 isconfigured to include a pair of nose pads 872, a first drug container orreservoir 874, and a second drug container or reservoir 876. First drugreservoir 874 and second drug reservoir 876 are configured to contact apatient or subject's ABTT terminuses 10 when device 860 is positioned ona patient or subject's head, supported by the patient or subject's earsand nose. Nose piece is further configured to include at least one firstthermoelectric device 878 positioned adjacent or alongside first drugreservoir 874 and at least one second thermoelectric device 880positioned adjacent or alongside second drug reservoir 876 to heat theskin of ABTT terminuses 10 and to heat the drugs in first drug reservoir874 and second drug reservoir 876. Nose piece 868 can further include atleast one temperature sensor 882 to measure the temperature of nosepiece 868 in the area where first thermoelectric device 878 and secondthermoelectric device 880 are positioned. Device 860 may be configuredto include a plurality of electronic elements, including a power supply884, a transceiver, transmitter, or receiver 886 for communication witha separate electronic device 888, and a controller 890.

FIG. 76 is a perspective view of another active transdermal deliverydevice in accordance with an exemplary embodiment of the presentdisclosure, indicated generally at 892. Device 892 is configured as apair of eyeglasses, including a frame 894, lenses 896, and temple pieces898. Device 892 further includes a pair of nose pads 900, a first drugcontainer or reservoir 902, and a second drug container or reservoir904. First drug reservoir 902 and second drug reservoir 904 areconfigured to contact a patient or subject's ABTT terminuses 10 whendevice 892 is positioned on a patient or subject's head, supported bythe patient or subject's ears and nose. Device 892 may be configured toinclude thermoelectric devices (not shown) adjacent to first drugreservoir 902 and second drug reservoir 904, similar to, for example,the configuration shown in FIGS. 73 and 75. Device 892 is furtherconfigured to include one or more temperature sensors 906 positioned tomeasure ambient temperature and temperature of frame 894. Device 892contains other electronic elements, such as a display screen 908; earbuds 910 configured to transmit information regarding drug delivery andother information to a subject or user; a power supply 912 configured toprovide power to electronic elements of device 892; a controller 914; atransceiver, transmitter, or receiver 916 configured to communicate witha separate electronic device 918; and a connector 920 configured topermit attachment of another separate electronic device 922, such as alaptop, cell phone, tablet, watch, etc. by way of a cable 924 andconnector 926.

FIG. 77 is a view of an active transdermal delivery device in the formof a nose clip, in accordance with an exemplary embodiment of thepresent disclosure, indicated generally at 928. Device 928 includes asupport 930 on which is positioned a first drug container or reservoir932. To control drug delivery through ABTT terminus 10, a firstthermoelectric device 934 is positioned adjacent to first drug container932, and to monitor the temperature of device 928, a first temperaturesensor 936 is positioned near first drug container 932, but a spaceddistance from first thermoelectric device 934. First drug container 932is configured to deliver a single drug to an associated first ABTTterminus 10. Device 928 is configured to include a second drug container938 and a third drug container 940 positioned side-by-side over anassociated second ABTT terminus 10. Device 928 further includes a secondthermoelectric device 942 positioned alongside, adjacent to, or next tosecond drug container 938, and a third thermoelectric device 944positioned alongside, adjacent to, or next to third drug container 940.Second thermoelectric device 942 is positioned to control the flow ofdrugs from second drug container 938 into second ABTT terminus 10, andthird thermoelectric device 944 is positioned to control the flow ofdrugs from third drug container 940 into second ABTT terminus 10. Thus,a single active transdermal delivery device, such as device 928, can beconfigured to deliver a plurality of different drugs to a patient orsubject 948. Device 928 can further include a second temperature sensor950 and a third temperature sensor 952 positioned adjacent to seconddrug container 938 and third drug container 940, respectively, tomonitor the temperature of each drug container.

Device support 930 further includes a first clip 954 and a second clip956 connected to each other by a bridge 958. Bridge 958 can beconfigured to include a plurality of electronic elements, such as acontroller 960; a transceiver, transmitter, or receiver 962 configuredto communicate with a separate electronic device 964, such as a laptop,tablet, cell phone, watch, etc.; and a power supply 966.

FIG. 78 is a cross-sectional view of an active transdermal deliverydevice in accordance with an exemplary embodiment of the presentdisclosure, indicated generally at 968. Device 968 includes a housingassembly 970. Housing assembly 970 includes a side wall 972, which canbe configured as an annulus, an upper cover 974, and a lower housingmember 976. Lower housing member 976 includes a plurality of openings978 formed therein. Housing assembly 970 forms an internal cavity,volume, or chamber 980, in which are positioned an actuation device 982and an absorbent material 984. Absorbent material 984 is configured toextend into plurality of openings 978 such that a bottom surface 988 ofabsorbent material 984 is approximately parallel to a bottom surface 986of lower housing member 976.

A removable or peelable layer 994 covers at least a portion of bottomsurface 986 of lower housing member 976 and bottom surface 988 ofabsorbent material 984. Separation of removable layer 994 exposes bottomsurface 988 so that bottom surface 988 can be accessible for contactwith ABTT terminus 10.

Device 968 includes a movable fluid passage 990 that extends through anopening 992 formed in upper cover 974. As will be seen, fluid passage990 is secured to an element of actuation device 982 and is movable bythe operation of actuation device 982. A seal 1002 is positioned onlower housing member 976 so that when actuation device 982 operates,movable fluid passage 990 contacts seal 1002 and prevents the movementof fluid from movable fluid passage 990 into absorbent material 984.When actuation device 982 is released, fluid, e.g., a drug, is able toflow from movable fluid passage 990 into absorbent material 984.

Actuation device 982 includes a coil 996 and a movable plate 998 biasedtoward a top of internal cavity 980 by one or more bias springs 1000.When actuation device 982 is operated, such as by an external controller1004 by way of a wireless connection or a wire or cable 1006, movableplate 998 is pulled toward a top surface 1008 of induction coil 996,which pulls fluid passage 990 downward toward seal 1002. Fluid passage990 makes contact with seal 1002 just before movable plate 998 makescontact with induction coil 996, preventing a flow of fluid 1012, e.g.,a drug, from a reservoir 1010 connected to movable fluid passage 990,blocking a flow of fluid 1012 to absorbent material 984. When actuationdevice 982 is released, movable plate 998 is released, moving an end offluid passage 990 away from seal 1002, permitting fluid 1012 to flowfrom reservoir 1010 through fluid passage 990 into absorbent material.Thus, actuation device 982 controls the flow of fluid 1012 intoabsorbent material 984, and then into an associated ABTT terminus 10and/or associated veins 14, 16, 18, 20, and 22. FIG. 79 is a view of anactive transdermal delivery device in accordance with an exemplaryembodiment of the present disclosure, indicated generally at 1014.Device 1014 includes a support 1016 in which is positioned a first drugcontainer 1018, and an annular thermoelectric device 1020 positioned ondevice support 1016. A second drug container 1022 is positioned in avolume 1024 formed within a central portion of annular thermoelectricdevice 1020. To protect first drug container 1018 and second drugcontainer 1022, device 1014 includes a removable or peelable layer (notshown) configured to cover at least first drug container 1018 and acover layer 1026 configured to cover at least second drug container1022.

When the removable layer is separated from device 1014, exposing firstdrug container 1018, and device 1014 is place on ABTT terminus 10, thedrugs in first drug container 1018, which are configured with a higherskin permeability than the drugs in second drug container 1022, providean immediate release of drugs to ABTT terminus 10. The drugs in seconddrug container 1022 are activated by heat from thermoelectric device1020, powered by a controller 1028 connected to thermoelectric device1020 by, for example, wires, or a cable 1030. Controller 1028 may beco-located with device 1014 or may be separately positioned.

Device 1014 is configured to provide a first release of drugs from firstdrug container 1018, typically at a first flow rate, and then to providea second release of drugs from second drug container 1022, often at alower flow rate that may be sustained for a period that is longer thanthe period for delivery of drugs from first drug container 1018.However, second drug container 1022 can be configured to deliver drugsat varying flow rates with the presence of thermoelectric device 1020,and can also be configured to deliver a second drug that is differentfrom a first drug positioned in first drug container 1018. It should beunderstood that first drug container 1018 can contain a skin permeationenhancer that increases skin permeability, and second drug container1022 contains a drug.

FIGS. 80-82 are views of a portion of a transdermal delivery device,which may be passive or active, incorporating a replaceable drugreservoir, in accordance with an exemplary embodiment of the presentdisclosure, indicated generally at 1032. Device 1032 includes a supportframe 1034, which can be, for example, an eyeglass frame. Support frame1034 includes nose pads 1036 to provide at least partial support forsupport frame 1034 on a subject or user's face. Support frame 1034 alsoincludes a longitudinally extending cavity or recess 1036 configured toreceive a separate reservoir 1038. Support frame 1034 further includes atransdermal drug delivery module 1040 positioned in a location such thatwhen support frame 1034 is located on the subject or user's head,transdermal drug delivery module 1040 is configurable to be positionedon the subject or user's ABTT terminus 10. Though not shown, it shouldbe understood that device 1032 is likely to include a second drugdelivery module 1040 for the subject's other ABTT terminus 10.

Transdermal drug delivery module 1040 includes a reservoir cavity 1042configured to contain a drug 1044, with reservoir cavity 1042 covered orenclosed by an absorbent material 1046 that permits drug 1044 flowtherethrough when in contact with an ABTT terminus 10 for transdermaldelivery of drug 1044 to the subject or patient. It should be understoodthat absorbent material 1046 can fill reservoir cavity 1042 in itsentirety. Thus, liquid separate from absorbent material 1046 may not bepresent in reservoir cavity 1042, and in this alternative embodiment(not shown) the liquid is contained and stopped at the level of fluidpassage 1052, thereby allowing better control of the delivery of drug1044 to absorbent material 1046. Transdermal drug delivery module 1040is connected or attached to support frame 1034 by a flexible arm 1048.Reservoir cavity 1042 is connected to separate reservoir 1038 by a firstfluid passage 1050 formed in support frame 1034, which is fluidlyconnected to a second fluid passage 1052 that extends through flexiblearm 1048 to connect with reservoir cavity 1042. Thus, when separatereservoir 1038 is positioned in support frame 1034, device 1032 isconfigured to provide an extended period of drug 1044 delivery to apatient or subject.

Separate reservoir 1038 may be fabricated from any suitable materialthat is inert with respect to drug 1044, which can include some types ofglass and plastic. Reservoir 1038 is covered at one end by a membrane1054 that seals drug 1044 in reservoir 1038 until reservoir 1038 isinstalled in support frame 1034. When reservoir 1038 is inserted intolongitudinally extending cavity 1036, a penetration or piercing device,apparatus, or mechanism 1056 punctures membrane 1054, permitting drug1044 to flow into first fluid passage 1050. Membrane 1054 extendingabout an end surface of separate reservoir 1038 serves as a seal toprevent leakage when separate reservoir 1038 is positioned in supportframe 1034. Alternatively, membrane 1054 can be removed or puncturedprior to installation in support frame 1034.

FIG. 83 is a perspective view of a separate drug reservoir in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 1058. While separate reservoir 1038 shown in FIGS. 80 and81 is beneficial in many gravity fed systems, providing an active pumpin association with a separate reservoir can be beneficial in sometransdermal delivery device configurations. Separate drug reservoir 1058includes a reservoir body 1060 that includes a cavity or volume forstorage of a drug. An end cap or cover 1062 encloses the cavity orvolume of reservoir 1058. In the exemplary embodiment of FIG. 83, endcap or cover 1062 includes a pump cap 1064 containing a small fluid pump1066 that may be formed, for example, by a MEMS process. A driver cap1068 configured to include a pump drive 1070 is configured to bepositioned on pump cap 1064. Pump drive 1070 is configured to be powerby an external power supply 1072 connected by wires or a cable 1074driver cap 1068 and then to pump drive 1070. Driver cap 1068 furtherincludes a fluid passage 1076 that connects fluid pump 1066 to, forexample, a transdermal drug delivery module.

FIG. 84 is a perspective view of a mask incorporating an activetransdermal delivery system in accordance with an exemplary embodimentof the present disclosure, indicated generally at 1078. Mask 1078includes a mask body 1080 configured to include an active transdermaldrug delivery system 1082, and a passive transdermal drug deliverydevice 1084.

Passive transdermal drug delivery device 1084 includes a first drugcontainer, which may be similar to drug container 466 shown in FIG. 40,positioned on a first angular extension 1086, and a second drugcontainer, which may be similar to drug container 468 shown in FIG. 40,positioned on a second angular extension 1088. The first drug containerand the second drug container in this embodiment are configured tocontact at least a portion of angular veins 20, and may extend tocontact at least a portion of facial veins 22. First angular extension1086 and second angular extension 1088 are preferably made with aflexible or conformable material for close apposition to the skinsurface overlying the veins. It should be understood that an adhesivesurface may be included in first angular extension 1086 and secondangular extension 1088 or on the skin surface of the first drugcontainer and the second drug container.

Active transdermal delivery device 1082 includes a plurality of drugreservoirs 1090 configured to mate with appropriately configuredreceptacles 1092 in mask body 1080. Drugs from any one drug reservoir1090 may be released upon command, such as through a control device 1094connected to mask 1078 wirelessly or by wires or a cable 1096.

FIG. 71 is a seventh graph demonstrating controlled drug flow in device1082 in accordance with an exemplary embodiment of the presentdisclosure. Because device 1082 can be configured to include a pluralityof different drugs, and delivery of each drug to ABTT terminus 10 can becontrolled, an infinite number of delivery times and quantities arepossible. For example, FIG. 71 plots the flow of three drugs A, B, and Cduring a twenty-four hour period. Drug A is provided during the firstsix hours, drug B is provided as shown in two intervals that do notoverlap with the interval of drug A, and drug C is provided throughoutthe twenty-four hour interval.

FIG. 85 is a perspective view of a portion of the active transdermaldelivery system of FIG. 84, showing drug reservoirs 1090 removed frommask body 1080. FIG. 86 is a cross-sectional view of the portion of FIG.85 along the lines 86-86. As shown in FIG. 86, mask 1078 furtherincludes a plurality of penetrating, puncturing, or piercing devices,apparatuses, or mechanisms 1098-1104, which are configured to pierce orpenetrate a membrane 1106 configured as a part of each drug reservoir1090 to seal a drug 1108 in reservoir 1090. Mask 1078 further includes aplurality of flow control valves 1110 configured to control the flow ofdrugs from drug reservoirs 1090 into a fluid passage 1112 formed in maskbody 1080. Once in fluid passage 1112, drugs flow into a flexible arm1114 configured to extend from mask body 1080 and terminating in a drugdelivery interface 1116. In the exemplary embodiment of FIGS. 84 and 86,flow control valves 1110 are electrically operated by way of controldevice 1094. In other embodiments, flow control valves 1110 may beoperated mechanically, electrically under the control of a timer, by anexternal program stored, for example, in a cell phone, and in otherways.

FIG. 87 is a perspective view of a puncture, piercing, or penetratingdevice compatible with the configuration of FIG. 86, in accordance withan exemplary embodiment of the present disclosure and indicatedgenerally at 1118. Device 1118 is configured with a penetrating,piercing, or puncturing first end 1120 configured to enter and extendthrough membrane 1106 when a reservoir, such as reservoir 1090, isinserted into a corresponding receptacle 1092. Device 1118 includes afirst opening 1122 and a second opening 1124 fluidly connected to firstopening 1122. In operation, a drug flows into first opening 1122,through a passage (not shown) internal to device 1118, and out fromsecond opening 1124, entering flow control valve 1110.

FIG. 88 is a perspective view of a puncture, piercing, or penetratingdevice compatible with the configuration of FIG. 86, in accordance withan exemplary embodiment of the present disclosure and indicatedgenerally at 1126. Device 1126 is configured with a penetrating,piercing, or puncturing first end 1128 configured to enter and extendthrough membrane 1106 when a reservoir, such as reservoir 1090, isinserted into a corresponding receptacle 1092. Device 1126 includes alongitudinally extending groove 1130. In operation, a drug flows intolongitudinally extending groove 1130 at first end 1128, and along groove1130 into flow control valve 1110.

FIG. 89 is a view of an active transdermal delivery system in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 1132. System 1132 is configured to include a capability toprovide a drug when authorized by an authorized practitioner, such as adoctor. System 1132 includes a transdermal drug delivery module 1134fluidly connected to a drug reservoir 1136. An electrically actuatedvalve 1138 is positioned along a fluid passage 1140 extending betweendrug delivery module 1134 and drug reservoir 1136. Valve 1138 isconfigured to be opened and closed in response to a command from acontroller 1142 configured as a part of system 1132. In the embodimentof FIG. 89, controller 1142 can be operated from a control panel 1144,which may be configured as a part of controller 1142, or wirelessly by aseparate electronic device 1146, such as a tablet, cell phone, laptop,and the like. System 1132 further includes a monitoring device 1148configured to read signals from ABTT terminus 10. Monitoring device 1148can be, for example, an infrared sensor or a temperature sensorconfigured to read the output from ABTT terminus 10. Output signalscorresponding to the signals output from ABTT terminus 10 are providedto controller 1142. Control panel 1144 further includes an indicatorlight 1150. As will be seen, system 1132 provides benefits in remote andvoluntary treatment of patients.

FIG. 90 is a drug delivery process flow of the system of FIG. 89 inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 1152. Process 1152 begins with a start process1154. In start process 1154, system 1132 is powered, drug reservoir 1136is filled with a drug and installed in system 1132, transdermal deliverymodule 1134 is positioned on a patient or subject's first ABTT terminus10, and monitoring device 1148 is positioned on a patient or subject'ssecond ABTT terminus 10. Once start process 1154 is complete, controlpasses from start process 1154 to a request authorization process 1156.

In request authorization process 1156, a patient, subject, or designatedperson requests authorization for the drug in reservoir 1136 to beprovided to the patient or subject. Such request may be by phone,internet, in person, etc. Once the request is submitted, control passesfrom request authorization process 1156 to a practitioner authorizationprocess 1158.

In practitioner authorization process 1158, a doctor, nurse, physician'sassistant, or other legally authorized person transmits authorizationfor a particular patient to system 1132. Such transmission may bewireless, such as by separate electronic device 1146, by entry directlyinto control panel 1144, or by other apparatus. Once a legallyauthorized person has approved the drug use, control passes frompractitioner authorization process 1158 to an indicator process 1160,where an indicator, such as indicator 1150 on control panel 1144,indicates that drug authorization has been received. Control then passesfrom indicator process 1160 to a patient authorization process 1162.

In patient authorization process 1162, a patient determines the need forthe drug, and activates delivery by way of control panel 1144,wirelessly, or through other apparatus. Control then passes from patientauthorization process 1162 to a patient monitoring process 1164.

In patient monitoring process 1164, system 1132 receives data from amonitoring device, such as a blood pressure monitor, a heart ratemonitor, an oximeter, an electrocardiogram (EKG), anelectroencephalogram (EEG), and the like. In the exemplary embodiment ofFIG. 89, the monitoring device is ABTT monitoring device 1148. Controlthen passes from patient monitoring process 1164 to a monitor dataanalysis process 1166. In monitor data analysis process 1166, system1152 determines, in view of signals from a monitor, such as ABTTmonitoring device 1148, whether the patient is the correct patient byanalysis of the thermal signature of the patient, and whether thepatient requires the drug. Control then passes from monitor dataanalysis process 1166 to a drug required decision process 1168.

In drug required decision process 1168, system 1132 determines whetherthe authorized drug is required, in view of the analysis conducted inmonitor data analysis process 1166. If the drug is not required, controlpasses from drug required decision process 1168 to patient monitoringprocess 1164, and process 1152 continues as previously described. If thedrug is required, control passes from drug required decision process1168 to a drug delivery process 1170.

In drug delivery process 1170, valve 1138 is opened and the drug inreservoir 1136 is delivered to ABTT terminus 10 by transdermal deliverymodule 1134. Control then passes to an additional drug available process1172.

In additional drug available process 1172, system 1132 determineswhether an additional dosage of the drug is available, which can beaccomplished by determining the amount originally provided in reservoir1136, less delivered amounts, by visual sensors, and the like. If anadditional dose of drug is available, control passes from additionaldrug available process 1172 to a dose authorized process 1174.

In dose authorized process 1174, process 1152 determines whether anadditional dose has been authorized. If an additional dose has beenauthorized, control passes from dose authorized process 1174 to patientmonitoring process 1164, and process 1152 continues as previouslydescribed. If an additional dose has not been authorized, control passesto a practitioner authorization required process 1176, where anindicator, such as indicator 1150 on control panel 1144, indicates theneed for a legally authorized practitioner, such as a doctor,physician's assistant, nurse, and the like, as permitted by law, toauthorize another dose of the drug in reservoir 1136. Control thenpasses from practitioner authorization required process 1176 to an endprocess 1180, which terminates process 1152.

Returning to additional drug available process 1172, if an additionaldosage is not available, control passes from process 1172 to a drugdepleted process 1178, in which an indicator, such as indicator 1150 oncontrol panel 1144, indicates the need to replenish the drug inreservoir 1136. Control then passes to end process 1180, whichterminates process 1152.

It should be apparent that process 1152 is beneficial in that it allowsa patient to have ready access to drugs when authorized by apractitioner, without the need to return to a pharmacy constantly.Furthermore, by monitoring a patient through ABTT terminus 10, apractitioner is able to verify a patient's condition prior toauthorizing delivery of the drug in reservoir 1136, increasing theefficiency of medical care, and reducing costs. It should be understoodthat other medical monitoring devices, such as blood pressuremonitoring, heart rate monitoring, oximetry, Electrocardiogram (EKG),electroencephalogram (EEG), and the like, can provide a feedback loop tosystem 1132. In this feedback loop embodiment, the signal from othermedical devices may control automatically, by increasing drug flow ordecreasing drug flow, the drugs being administered transdermally bysystem 1132.

FIG. 91 is another drug delivery process flow of the system of FIG. 89in accordance with an exemplary embodiment of the present disclosure,indicated generally at 1182. Process 1182 begins with a start process1184. In start process 1184, system 1132 is powered, drug reservoir 1136is filled with a drug and installed in system 1132, transdermal deliverymodule 1134 is positioned on a patient or subject's first ABTT terminus10, and monitoring device 1148 is positioned on a patient or subject'ssecond ABTT terminus 10. Once start process 1184 is complete, controlpasses from start process 1184 to a request authorization process 1186.

In request authorization process 1186, a patient, subject, or designatedperson requests authorization for the drug in reservoir 1136 to beprovided to the patient or subject. Such request may be by phone,internet, in person, etc. Once the request is submitted, control passesfrom request authorization process 1186 to a practitioner authorizationprocess 1188.

In practitioner authorization process 1188, a doctor, nurse, physician'sassistant, or other legally authorized person transmits authorizationfor a particular patient to system 1132. Such transmission may bewireless, such as by a separate electronic device 1146, such as, forexample, a cell phone, by entry directly into control panel 1144, or byother apparatus. Once a legally authorized person has approved the druguse, control passes from practitioner authorization process 1188 to anindicator process 1190, where an indicator, such as indicator 1150 oncontrol panel 1144, indicates that drug authorization has been received.Control then passes from indicator process 1190 to a patientauthorization process 1192.

In patient authorization process 1192, a patient determines the need forthe drug, and activates delivery by way of control panel 1144,wirelessly, or through other apparatus. Control then passes from patientauthorization process 1192 to an additional dosage authorized process1194, where process 1182 determines whether the practitioner hasauthorized an additional dosage. If an additional dosage has beenauthorized, control passes from additional dosage authorized process1194 to a predetermined interval process 1198. If an additional dosageis not authorized, control passes from additional dosage authorizedprocess 1194 to an end process 1196, which terminates process 1182.

In predetermined interval process 1198, system 1132 measures apredetermined passage of time such as, for example, four, six, eight,twelve, or twenty-four hours. If the predetermined interval has yet tobe reached, process 1198 continues in a loop until the predeterminedtime interval is reached, after which control passes from predeterminedinterval process 1198 to an automatic drug delivery authorizationprocess 1200.

In automatic drug delivery authorization process 1200, process 1182determines whether the patient has authorized automatic delivery of thedrug in reservoir 1136. If automatic delivery has been authorized,control passes to a drug delivery process 1202, where the drug isdelivered. Control then passes from drug delivery process 1202 toadditional dosage process 1194, and process 1182 continues as previouslydescribed. If automatic delivery has not been authorized, control passesfrom automatic drug delivery authorization process 1200 to patientauthorization process 1192, and process 1182 continues as previouslydescribed herein.

A benefit to process 1182 is that automatic delivery of drugs to ABTTterminus 10 can occur without a need for a patient to remember that itis time for another dosage. Further, delivery can, as with process 1152,be remotely authorized by a legally authorized practitioner, providing asafe, fast, efficient, process for authorizing and delivering drugs to apatient.

FIG. 92 is another transdermal delivery system in accordance with anexemplary embodiment of the present disclosure, indicated generally at1204. System 1204 includes a support device 1206 on which is positioneda transdermal drug delivery module 1208 and a plurality ofaccelerometers or other motion detection devices 1210. Transdermal drugdelivery module 1208 includes one or more drug containers 1212configured to deliver a drug to a respective ABTT terminus 10. Drugcontainers 1212 are connected to a reservoir and flow control apparatus1214 configured to supply a drug to drug containers 1212 by way of fluidpassages 1216, when commanded by a controller 1218 positioned on supportdevice 1206. Controller 1218 may include a transceiver, transmitter, orreceiver (not shown), or such may be provided separately on supportdevice 1206, which is configured to communicate with a separateelectronic device 1220 for monitoring of a patient 1222 and control ofsystem 1204. Controller 1218 further includes an integral timer or clockthat can be configured to include a timer or timing function, includingwake alarms. Timer-related alarms in controller 1218 can be set by wayof, for example, separate electronic device 1220 when separateelectronic device 1220 is configured with the appropriate interfacesoftware. System 1204 may also include a wrist band 1224 that includesone or more motion detection devices 1210. Wrist band 1224 maycommunicate with controller 1218 by a cable or wire (not shown) orwirelessly.

System 1204 is configured to provide one or more drugs to patient 1222when needed for a condition that generates certain characteristicmotions that can be detected by motion detection devices 1210. Suchcharacteristic motions can include semi-wakefulness for sleep disordersand seizures. Wrist band 1222 can be beneficial for some conditionsbecause hand movements are sometimes an indication of an imminentcondition.

FIG. 93 is a sleep treatment process of the system of FIG. 92, indicatedgenerally at 1226. Process 1226 begins with a start process 1228, wherepower may be provided to system 1204, which can be properly positionedon patient 1222, drugs can be provided to reservoir and flow controlapparatus 1214, and other actions necessary to prepare system 1204 andprocess 1226 for operation. Once start process 1228 is complete, controlpasses from start process 1228 to a receive motion sensor data process1230.

In receive motion sensor data process 1230, controller 1218 receivessignals from motion detection devices 1210. Control then passes fromreceive motion sensor data process 1230 to an analyze data process 1232.After analysis of motion sensor data, control passes to a semi-awakestate decision process 1234, where process 1226 determines whether thesignals provided by motion detection devices 1210 is indicative of asemi-awake state that is likely to lead to an awakened state. If asemi-awake state is not indicated, control passes from semi-awake statedecision process 1234 to a predetermined wake time decision process1236.

In predetermined wake time decision process 1236, system 1204 determineswhether a predetermined wake time has been reached. The predeterminedwake time can be set, for example, by way of separate electronic device1220, using a timer or clock internal to controller 1218. In order todecrease the effect of a drug after awakening, the predetermined waketime can be a time after which no drugs are provided, even if asemi-awake state is reached. Thus, if a patient or subject plans toawaken at, for example, 6 AM, the predetermined “wake time” can be setfor 4 AM, and no drugs will be administered after that time. Thus, thepredetermined “wake time” can be consider a time at which theadministration of drugs is stopped. If such a time has been reached,then control passes from predetermined wake time decision process 1236to an end process 1238, where process 1226 terminates and patient 1222is permitted to awaken. If the predetermined wake time has not beenreached, control passes from predetermined wake time decision process1236 to receive motion sensor data process 1230, and process 1226continues as previously described herein.

Returning to semi-awake state decision process 1234, if a semi-awakecondition is detected that is likely to lead to awakening, controlpasses from semi-awake state decision process 1234 to a conditiondecision process 1240, where the condition of patient 1222 is determinedfrom at least motion detection sensors 1210. If an abnormal condition isindicated, control passes from condition decision process 1240 to analarm process 1244, where one or more alarms are actuated, which caninclude an alarm to separate electronic device 1220. Control then movesfrom alarm process 1244 to end process 1238, where process 1226terminates.

Returning to condition decision process 1240, if an abnormal conditionis not detected, control passes from condition decision process 1240 toa sleep compound delivery process 1242, where a drug is delivered byreservoir and flow control apparatus 1214 to drug containers 1212 by wayof fluid passages 1216, which should return patient 1222 to a conditionof sleep. Control then passes from sleep compound delivery process 1242to receive motion sensor data process 1230, where process 1226 continuesas previously described herein.

FIG. 94 is a view of a retroauricular drug delivery device in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 1246. Device 1246 is configured to connect or attach to atemple frame 1248, which may be a portion of, for example, a pair ofeyeglasses. Device 1246 includes a fastening arrangement 1250 configuredto mate with a complementary fastening arrangement 1252 on temple frame1248. Device 1246 further includes a drug container 1254 positioned on aflexible arm 1256, which permits adjustment of the position of drugcontainer 1254 to match the position of a retroauricular vein positionedbehind a patient or subject's ear for transdermal drug delivery to theretroauricular vein. Delivery of drugs to the retroauricular vein isbeneficial for certain conditions, such as motion sickness. An advantageof this embodiment includes a lack of adhesive surface, or if anadhesive surface is present it can contain a weak adhesive, by virtue ofthe end of the temples pressing the surface containing drug against theskin. This embodiment is clinically useful since the retroauricular skinis sensitive and can be easily damaged by an adhesive or even moreseverely by a strong adhesive.

FIG. 95 is a view of another retroauricular drug delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 1258. Device 1258 is configured to connect orattach to a temple frame 1260, which may be a portion of, for example, apair of eyeglasses. Device 1258 includes a fastening arrangement 1262,configured as screw threads, to mate with a complementary fasteningarrangement 1264 on temple frame 1260. Device 1258 further includes adrug container 1266 positioned on a flexible arm 1268, which permitsadjustment of the position of drug container 1266 to match the positionof a retroauricular vein positioned behind a patient or subject's earfor transdermal drug delivery to the posterior auricular vein, alsoreferred to in the present disclosure as the retroauricular vein. Itshould be understood that a sliding mechanism, telescopic mechanism, andthe like can be included as part of arm 1268 in order to allow precisepositioning of drug containing surface on the posterior auricular veinand/or stylomastoid vein.

FIG. 96 is a view of yet another retroauricular drug delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 1270. A portion of device 1270 is cut away toreveal certain features of device 1270. Device 1270 is configured toconnect or attach to a temple frame 1272, which may be a portion of, forexample, a pair of eyeglasses. Device 1270 includes a fasteningarrangement 1274, configured as a cavity 1276 that is configured toinclude a compressible material 1278. When device 1270 is pushed ontotemple frame 1272, compressible material 1278 grips temple frame 1272,securing device 1270 to temple frame 1272. Device 1270 further includesa drug container 1280 positioned on a flexible arm 1282, which permitsadjustment of the position of drug container 1280 to match the positionof a posterior auricular vein positioned behind a patient or subject'sear for transdermal drug delivery to blood vessels located behind theear. Device 1270 further includes a thermoelectric device 1284positioned to heat drug container 1280 and the skin over theretroauricular vein. Device 1270 is also configured to include a powersupply 1286, and may include a controller 1288 and a transceiver,transmitter, or receiver 1290 for communication with a separateelectronic device 1292.

FIG. 97 is a view of a further retroauricular drug delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 1294. Device 1294 is configured to be positionedon a subject or patient's ear. Device 1294 includes a support 1296; adrug container 1298 positioned on a flexible arm 1300, which permitsadjustment of the position of drug container 1298 to match the positionof a vein positioned behind a patient or subject's ear for transdermaldrug delivery to a vein positioned behind a patient or subject's ear; athermoelectric device 1302 positioned adjacent to drug container 1298; areservoir 1304 and a flexible fluid passage 1306 connecting reservoir1304 to drug container 1298; and a plurality of electronic elements. Theplurality of electronic elements can include a power supply 1308,controller 1310, and a transceiver, transmitter, or receiver 1312 forcommunication with a separate electronic device 1314. It should beunderstood that device 1294 may not include a separate reservoir 1304and flexible fluid passage 1306, and in this embodiment device 1294includes an ear supported device having a support 1296 and a drugcontainer 1298, said drug container being passive or active, the latterincluding a thermoelectric device. In this embodiment, drug container1298 can be an extension of support 1296, with no connecting arm 1300 tosaid drug container 1298 being necessary.

FIG. 98 is a view of a yet further retroauricular drug delivery devicein accordance with an exemplary embodiment of the present disclosure,indicated generally at 1316. Device 1316 is configured to connect orattach to a temple frame 1318, which may be a portion of, for example, apair of eyeglasses. Device 1316 includes a fastening arrangement 1320,configured as hooks, clips and the like, to mate with temple frame 1318.Device 1258 is further configured to include a drug container 1322positioned on a flexible arm 1324, which permits adjustment of theposition of drug container 1322 to match the position of a posteriorauricular vein positioned behind a patient or subject's ear fortransdermal drug delivery to the posterior auricular vein. Device 1258is yet further configured to include a powered transceiver, transmitter,or receiver 1326 configured to communicate with a separate electronicdevice 1328.

FIG. 99 is a view of a pair of eyeglasses, indicated generally at 1330,configured to include a retroauricular drug delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated at 1332. Device 1332 is attached to a temple frame 1334 ofeyeglasses 1330 by a flexible arm 1336, which permits adjustment of theposition of device 1332 to match the position of a retroauricular veinpositioned behind a patient or subject's ear for transdermal drugdelivery to the retroauricular vein. Device 1332 further includes a drugcontainer 1338.

FIG. 100 is a view of a tear diagnostic system in accordance with anexemplary embodiment of the present disclosure, indicated generally at1340. Certain drugs administered through ABTT terminus 10 and theretroauricular vein can be detected through tears in the eye. Thus,closed loop feedback system 1340 can be configured with a detector 1342positioned, for example, on a contact lens 1344 that is then positionedon an eye 1346. Detector 1342 detects a level of a chemical or drug ineye 1346, and transmits that information wirelessly to an activetransdermal drug delivery device or module 1348, which then adjusts therate of drug flow through ABTT terminus 10 accordingly.

FIG. 101 is a view of another tear diagnostic system in accordance withan exemplary embodiment of the present disclosure, indicated generallyat 1350. System 1348 includes a detector 1352 positioned, for example,on a contact lens 1354 that is then positioned on an eye 1356. Detector1352 detects a level of a chemical or drug in eye 1356, and transmitsthat information wirelessly to an active transdermal drug deliverydevice or module 1358 positioned on an eyeglass frame 1360, which thenadjusts the rate of drug flow through ABTT terminus 10 accordingly. Itshould be understood that module 1358 can be positioned in any othersupport located in other parts of the body, and in other devices, suchas the various embodiments described herein as clips, patches, masks,head gear, and the like.

FIG. 102 is a view of another active transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 1362. Device 1362 is configured to include asupport structure 1364, and a head support apparatus 1366.

Support structure 1364 includes a drug container 1368 positioned on,over, or adjacent the skin of ABTT terminus 10, at least one drugcontainer 1370 positioned on, over, or adjacent the skin over superiorpalpebral vein 16, and at least one drug container 1372 positioned on,over, or adjacent the skin over frontal vein 20 and, in an alternativeembodiment, over facial vein 22. It should be understood that drugcontainers 1368, 1370, and 1372 can be configured to include a same drugor a plurality of drugs. Support structure 1364 further includes aplurality of thermoelectric devices 1374 positioned in along supportstructure 1364. As described herein, by heating or cooling the skin,drug flow into associated veins is moderated or modified because thepermeability of skin is related to temperature, and thermoelectricdevices 1374 can both heat and cool. However, it should be understoodthat other temperature modification devices can be used in place ofthermoelectric devices 1374, such as resistive heaters. Supportstructure 1364 can also be configured to include at least onetemperature sensor 1376 to measure the temperature of support structure1364, the temperature of one or more drug containers, or the temperatureof the skin.

Head support apparatus 1366 is configured to include a controller 1378and a power supply 1380 configured to provide power to the electronicelements of device 1362. Head support apparatus 1366 can also include acontrol panel or operator input device, or can also include atransceiver, transmitter, or receiver 1382 configured to communicatewith a separate electronic device 1384, wherein separate electronicdevice 1384 is configured to operate device 1362. Controller 1378 cancommunicate with the electronic elements positioned on support structure1364 wirelessly, or through a wire or cable 1386.

FIG. 103 is a view of a face showing locations for application ofpassive or active transdermal delivery devices, in accordance with anexemplary embodiment of the present disclosure. As described herein,passive and active devices can be positioned in a nearly infinite numberof locations and combination of locations. However, it should beunderstood that the present disclosure also includes placement ofpassive and active transdermal devices on one or more veins or locationsthat feed, provide, direct, or guide blood to ABTT 12. For example, andas shown in FIG. 103, a passive or active transdermal delivery device1388 can be positioned along either frontal vein 14, supraorbital vein18, or both, a passive or active transdermal delivery device 1388 can bepositioned along superior palpebral vein 16, and a passive or activetransdermal delivery device can be positioned along angular vein 20 orfrontal vein 22, without placement of a transdermal delivery device overABTT terminus 10. The benefit to such placement is naturally modifyingthe rate of drug delivery to the brain rather than doing so withpermeability modification apparatus or chemicals.

FIG. 104 is a view of a face showing additional locations available forplacement of an active or a passive transdermal delivery device, inaccordance with an exemplary embodiment of the present disclosure. Aface 1394 shows placement of a passive or active transdermal deliverydevice 1396 on a roof of an orbit 1398, which may also be described asbeing under the eyebrow, or under the ridge of the brow. Face 1394 alsoshows placement of a passive or active transdermal delivery device 1400on a side of nose 1402.

Active embodiments of the present disclosure describe heating or coolingof portions of faces for transdermal delivery. These embodiments includethermoelectric devices, chemical heating and cooling, and resistiveheating. FIG. 105 shows a schematic view of an active transdermaldelivery device in accordance with an exemplary embodiment of thepresent disclosure, indicated generally at 1404. Device 1404 includes adrug container 1406 surrounded by a resistive heater 1408. Resistiveheater 1408 is connected to a controller or power supply 1410 by a wireor cable 1412. Generally, thermoelectric devices provide the mostcapability given that they can heat or cool and are relatively accurate.Resistive devices are capable of heating only, and controlling suchdevices as precisely as thermoelectric devices typically requires morecomplex electronics than is necessary for thermoelectric devices.However, any heating or heating and cooling device can be used with theactive devices disclosed herein as long as such devices can providelocalized heating and cooling needed to control drug permeation throughthe skin.

One experimental technique used by Applicant to verify the efficacy ofthe systems, apparatuses, devices, processes, and methods disclosedherein was to compare absorption of a chemical into the blood stream.The chosen chemical was caffeine, and a comparison was made betweendistribution of caffeine in the body from a 15 mm by 15 mm patch placedon ABTT terminus 10 and a 15 mm by 15 mm patch placed on an upper arm.Caffeine concentration was measured in the same location on the body. Asshown in FIG. 106, curve 1414 shows caffeine concentration with time fora caffeine patch positioned on the upper arm, and curve 1416 showscaffeine concentration with time for a caffeine patch positioned on ABTTterminus 10. As is evident from FIG. 106, the peak concentration ofcaffeine from the patch placed on the arm occurred five hours afterplacement of the patch, which peak concentration from the patch placedon ABTT terminus 10 was about 30 minutes after placement of the patch.Furthermore, peak concentration from placement of the patch on ABTTterminus 10 was more than twice as high as peak concentration fromplacement of the patch on the upper arm. Other compounds tested showsimilar results. Thus, the systems, apparatuses, devices, processes, andmethods of the present disclosure, in addition to being novel, aresignificantly more effective than conventional application oftransdermal patches. In addition, it should be noted that use of a knownpatch would be disadvantageous if applied to ABTT terminus 10, because alesser quantity of a drug is required to achieve the same results. Infact, a conventional patch could prove to be dangerous if applied toABTT terminus 10 due to the presence of a much higher quantity of drugthan is required in combination with the high permeability of ABBTterminus 10, and the direct connection between ABTT terminus 10 and thebrain. In order to achieve the same effect at ABTT terminus 10 asapplication of a conventional patch in a conventional application, onlyabout ⅔ the quantity of a drug is required for the same effect at ABTTterminus 10.

FIG. 107 is a perspective view of another transdermal delivery device inaccordance with an exemplary embodiment of the present disclosure,indicated generally at 1418. Device 1418 is configured as an eyeglassframe 1420. Frame 1420 includes nose pads 1422, each of which isconfigured to include a drug container 1424 for placement on a portionof a nose and adjacent face, and a posterior auricular extension 1428attach to or positioned on a temple frame 1430. Each posterior auricularextension 1428 includes a drug container 1432 configured to bepositioned in contact with a posterior auricular vein when eyeglassframe 1420 is worn on a face. Each posterior auricular extension 1428 isconfigured to be slidable or adjustable on a respective temple frame1430 by an adjustment arrangement or configuration 1434 to provideadjustment of each posterior auricular extension 1428 to match theposition of drug container 1432 to a respective auricular vein.

FIG. 108 is a view of a transdermal delivery device in accordance withan exemplary embodiment of the present disclosure, indicated generallyat 1436. Device 1436 includes adhesive and drug contained wings 1438positioned on either side of a nose 1440. Wings 1438 can be configuredto extend along angular vein 20 and frontal vein 22 by providing wings1438 with added area 1446, shown with dashed lines. Wings 1438 areconnected by a transversely extending bridge 1442, including a cover1444. Cover 1444 is configured to be an area for printing, and indeed,the entire outer portion of device 1436, can be configured to provide asurface for writing or printing. By providing an area for writing, thedrug or drugs included in device 1436 can be written or printed thereon,making such readily visible to an observer of device 1436.Alternatively, cover 1444 can include pre-printed information, such asthe types and dosage of included drugs, along with permeation enhancers,if any. Furthermore, cover 1444 can include an advertisement for aproduct, for device 1436, artistic expression, etc. Thus, cover 1444 isa highly functional feature of device 1436.

FIG. 109 is a view of a transdermal delivery device in accordance withan exemplary embodiment of the present disclosure, indicated generallyat 1448. Device 1448 is configured to include a support 1450, which isconfigured to include a removable and replaceable drug container orpatch 1452 and a plurality of electronics. The plurality of electronicscan include a power supply 1454, a controller 1456, and a transceiver,transmitter, or receiver 1458, configured to communicate with a separateelectronic device 1460, such as a cell phone, laptop, tablet, etc.,which can also be configured to communicate with yet another separateelectronic device 1462, such as a cell phone, table, laptop, etc.Support 1450 can also be configured with a permeability modificationdevice or apparatus, such as a thermoelectric device 1464.

FIG. 110 is a view of a transdermal delivery system in accordance withan exemplary embodiment of the present disclosure, indicated generallyat 1466. System 1466 includes a transdermal delivery device 1468, whichcan be configured similar to device 1448 shown in FIG. 109, a sensor1470, which can be any one of a plurality of sensors to measure variousattributes of a body, such as oximetry, heart rate, blood pressure,glucose, and the like, and a sensor display or sensor controller 1472.Sensor controller 1472 can be configured to communicate with device 1468to provide feedback to device 1468, which can then use that feedback toincrease or decrease the rate of drug flow in a drug container to thepatient or subject.

FIG. 111 is a view of a transdermal delivery system in accordance withan exemplary embodiment of the present disclosure, indicated generallyat 1474. System 1474 includes a support 1476 configured as a headband,on which are positioned at least one passive or active transdermaldelivery device 1478, 1480, 1482, and 1484. Transdermal delivery devices1478, 1489, 1482, and 1484 are configured to be replaceable.

FIG. 112 is a view of a transdermal delivery system in accordance withan exemplary embodiment of the present disclosure, indicated at 1486.System 1486 includes a support 1488 configured as a headband, includingat least one passive or active transdermal delivery device 1488positioned thereon.

FIG. 113 is a view of a transdermal delivery device in accordance withan exemplary embodiment of the present disclosure, indicated generallyat 1492. Similar to the device of FIG. 46, device 1492 includes anannular drug container or ABTT interface 1494 with a central opening1496 in which is positioned a circular thermoelectric device 1498. Asshown in FIG. 114, this configuration is advantageous because heat isdistributed uniformly throughout drug container 1494, and drugs fromdrug container 1494 flow over a larger area than in designs of a similarsize where the thermoelectric device is annular and the drug containeris positioned in a central opening of the thermoelectric device.

While the present disclosure has been focused on humans to this point,animals have a similar, though less effective, passage between the brainand the surface that is described as an intracranial thermal path (ITP).For example, FIG. 115 shows an animal, such as a dog 1500. Dog 1500includes an ITP (not shown) that extends from the dog's brain to an ITPterminus 1502 positioned adjacent to an eye 1504 of dog 1500. As thedisclosed embodiments presented herein benefit humans, modifications ofthe devices presented herein can be modified to interface with ITPterminus 1502 for benefit to animals. For example, FIG. 115 shows atransdermal drug delivery system in accordance with an exemplaryembodiment of the present disclosure and indicated generally at 1506.

Animals may have fur and fat insulation that reduces thermalconductivity, shifting the position of the equivalent of ABTT terminus10 in animals to ITP terminus 1502, which is represented by an area oftransition skin-mucosa located in the corner of the eye, frequentlyadjacent to the tear duct and caruncle or conjunctival surface andreferred to herein as the transition area. In some species, such ascanines, felines and other predators, the transition area or ITPterminus 1502 is located in the anterior or medial portion of the cornerof the eye; in swine, ITP terminus 1502 tends to be located in theposterior or lateral corner of the eye; in ovine, bovine and equines,ITP terminus 1502 tends to be located in the anterior corner of the eye;and in primates such as chimpanzees, ITP terminus 1502 tends to belocated in both the medial corner and the lateral corner of the eye.

In the exemplary embodiment of FIG. 115, transdermal delivery system1506 includes an ITP interface 1508 configured to include a drugcontainer 1510, which is configured to interface with ITP 1502, and athermoelectric device 1512 configured to heat or cool the drug in drugcontainer 1510 and/or ITP 1502 to control the permeability of the drug.Typically, because animals frequently object to the presence of objectsnear their eyes, transdermal drug delivery system 1506 includes aharness 1514 for attachment of drug delivery system 1506 to head 1528 ofanimal 1500. Harness 1514 is configured to position transdermal drugdelivery system 1506 over ITP terminus 1502. In the exemplary embodimentof FIG. 115, thermoelectric device 1512 is configured to be connected toa pack 1516 configured to be positioned, attached, secured, or mountedon animal 1500 to provide a location for one or more batteries 1518.Batteries 1518 are then connected to thermoelectric device 1512 by, forexample, wires or a cable 1520 extending between batteries 1518 and ITPinterface 1508. Transdermal drug delivery system 1506 may include acontroller 1522 configured to operate transdermal drug delivery system1506, and controller 1522 is configured to be programmed, adjusted, orset by a separate electronics device 1524, which can be wirelessly orthrough wires or a cable 1526. Separate electronics device 1524 can be adevice specifically configured to program, adjust, or set transdermaldrug delivery, or it can be, for example, a cell phone, laptop, tablet,watch, or the like.

FIG. 116 is a view of an animal wearing another transdermal deliverysystem in accordance with an exemplary embodiment of the presentdisclosure, indicated generally at 1530. System 1530 includes an ITPinterface 1532 positioned on harness 1514. ITP interface 1532 includes adrug container 1534 configured to be positioned on ITP terminus 1502when animal 1500 wears harness 1514.

FIG. 117 is a view of an ITP interface in accordance with an exemplaryembodiment of the present disclosure, indicated generally at 1536.Interface 1536 includes a drug container 1538 configured to interfacewith ITP 1502 when harness 1514 is positioned, attached, mounted, orlocated on animal 1500. Interface 1536 may be configured to include adrug container support 1540 that connects, attaches, supports, or mountsdrug container 1534 to harness 1514.

FIG. 118 is a view of a drug container 1538 of ITP interface 1532. Drugcontainer 1538 is configured to be supported in drug container support1540, and includes a backing layer 1542 and a drug 1544, which may belocated in an absorbent material. FIG. 119 is a cross-sectional view ofthe drug container of FIG. 118 along the lines 119-119.

FIG. 120 is a cross-sectional view of another intracranial thermal pathinterface in accordance with an exemplary embodiment of the presentdisclosure, indicated generally at 1546. ITP interface 1546 isconfigured to provide an easily removable module for the replenishmentor replacement of a drug. ITP interface 1546 is configured to bepositioned and supported in a harness 1548, and captured between aretention mechanism, device, or apparatus 1550 configured as a part ofharness 1548 and an ITP terminus 1552 of an animal. Retention mechanism1550 includes a retention plate 1554 configured to swing or rotation ona pivot pin 1556. Harness 1548 further includes a receptacle, opening,cavity, or the like 1558 configured to support a drug module 1560 of ITPinterface 1546.

Drug module 1560 includes a base plate 1562, a drug container support1564 connected to base plate 1562 by a bias spring 1566, and a drugcontainer or absorbent material 1568 positioned or supported on drugcontainer support 1564. When drug module 1560 is positioned and retainedin receptacle 1558, bias spring 1566 presses drug container or absorbentmaterial 1568 against ITP terminus 1552, permitting drug to flow fromdrug container or absorbent material 1568 into ITP terminus 1552 andthen into the brain of the animal.

FIG. 121 is a view of a transdermal delivery device positioned on a headof a subject or patient in accordance with an exemplary embodiment ofthe present disclosure, indicated generally at 1570. Device 1570includes a headband support 1572, and one or more face extensions 1574.Headband support 1572 is configured to contain a drug 1576 positionedalong a forehead area 1578 that, when headband support 1572 is attachedto forehead 1578, is in contact with portions of frontal vein 14 andsupraorbital vein 18, and, depending on the size and configuration ofheadband support 1572, possibly superior palpebral vein 16. Headbandsupport 1572 includes a strap 1580 configured to encircle a head 1582,thus securing headband support 1572 to head 1582. Face extensions 1574are configured to contain a drug in zones, regions, or portions 1584that extend down the sides of the nose and onto the cheek area, thuscovering a portion of angular vein 20 and extending into the region offacial vein 22. Face extensions 1574 comprise preferably convex orcomma, boomerang or banana shape configuration with nodes or ABTTinterfaces 1586 that will allow nodes 1586 to conform closely to thespecial topography of ABTT target area 10 and associated veins. Faceextensions 1574 contain one or more drugs and are configured to fitprecisely in the medial canthal area adjacent to the medial corner ofthe eye in the superomedial orbit, where ABTT target area 10 and theconvergence of four veins 14, 16, 18, and 20 is located. In an exemplaryembodiment, each face extension 1574 can include a strap (not shown)that extends beyond the facial/angular vein area to wrap around the headbelow the ears to fit each facial extension 1574 securely to the face.For both headband support 1572 and face extensions 1574 of device 1570,the opposite ends of strap 1580 and straps attached to face extensions1574 are configured to be fastened to one another to form a secure fit.In an exemplary embodiment, strap 1580 may be fastened using a hook andloop arrangement, but may also use snaps, buttons, ties, hooks,adhesive, or other fastening mechanism, device, or apparatus. Headbandsupport 1572 includes a strip of a fastening arrangement (not shown),which in an exemplary embodiment is a hook and loop arrangement, locatedin a region at the center of the headband support 1572. When worn by auser, the fastening arrangement will be located on the forehead directlybetween the eyebrows. Face extensions 1574 include a mating fasteningarrangement (not shown) located on an upper end 1588 that, whenpositioned on the face of a user, is located above the bridge of thenose. The fastening arrangement of each face extension 1574 isconfigured to mate and attach to the fastening arrangement of headbandsupport 1572. Once face extensions 1574 are attached to headband support524, the assembly forms transdermal delivery device 1570, which is onemask-like structure to cover vital areas related to ABTT 12. Thefastening arrangement of each face extension 1574 is smaller than thefastening arrangement of headband support 1572. This size differentialallows each face extension 1574 to be adjusted by moving face extensions1574 left or right, or up and down the face. This adjustableconfiguration allows transdermal drug delivery device 1570 to adapt tofit many different face types and shapes. For example, some people havelonger faces or broader noses. With an adjustable fastening arrangementsuch as hook and loop, and two separate portions, i.e., headband support1572 and face extensions 1574, transdermal drug delivery device 1570 maybe suitable for any number of wearers that have innumerable anatomicaldifferences. It should be understood that device 1570 may includethermoelectric devices configured to heat the drug or drugs inpositioned in device 1570.

FIG. 122 is a view of another transdermal delivery device in accordancewith an exemplary embodiment of the present disclosure, indicatedgenerally at 1590. Transdermal delivery device 1590 is formed of onepiece, rather than having separate headband and face portions. Device1590 is not as easily adjustable for size as some embodiments, buttransdermal drug transfer is still readily available, as device 1590covers at least one of the key venous areas; i.e., ABTT terminus 11 andthe areas of the skin over veins 14, 16, 18, 20, and 22. In thisembodiment, three to four different sizes are used to cover a wholerange of different head sizes.

Device 1590 includes a face portion 1592 and a forehead portion 1594.Dimensions, such as width of the bands covering the veins are important,otherwise drug transfer into the vein area is inefficient. In anexemplary embodiment, specialized preferred dimension of face portion1592, shown by arrows 1596, is 4.5 cm or less, preferably is 3.5 cm orless, and more preferably is 2.5 cm or less, and most preferably is 1.5cm or less, and yet most preferably is 1 cm or less. Specializedpreferred dimension of a nose portion 1598, shown by arrows 1600, is 3.7cm or less, and preferably 2.7 cm or less, and most preferably 1.7 cm orless, and yet most preferably 1.2 cm or less, and even most preferably 1cm or less. A specialized preferred dimension of forehead portion 1594,shown by arrows 1602, is 5.5 cm or less, is preferably 4.5 cm or less,is more preferably 3.5 cm or less, is even more preferably 2.5 cm orless, and is most preferably 2.0 cm or less. A specialized preferreddistance between a lower edge 1604 of forehead portion 1594 and an upperedge 1606 of facial portion 1592, shown by arrows 1608, is 10.5 cm orless, is preferably 9.5 cm or less, is more preferably 8.5 cm or less,is even more preferably 7.5 cm or less, and is most preferably 6.0 cm orless. A specialized preferred length of forehead portion 1594, shown byarrows 1610, is 17 cm or less, is preferably 14 cm or less, is morepreferably 12 cm or less, is even more preferably 10.5 cm or less, andis most preferably 9.5 cm or less.

FIGS. 123 to 126 show exemplary ABTT eyewear iontophoretic system withtwo structures, one structure having one arm as shown in FIG. 126, andanother structure having two arms, as shown in FIG. 123. FIG. 123 showsan ABTT iontophoretic eyewear in accordance with an exemplary embodimentof the present disclosure, indicated generally at 1650. ABTTiontophoretic eyewear 1650 includes a frame 1652, with frame 1652configured to include two arms 1654 and 1656, each arm configured toinclude a set of electrodes 1658 and 1660 represented by a workingelectrode in one arm and a passive electrode in the other arm, disposedas an anode and a cathode, electrodes 1658 and 1660 configured to belocated at an end of each arm 1656 and 1654, respectively, which areviewed in a magnified fashion in FIGS. 124 and 125. Frame 1652 is alsoconfigured to include a power source 1662, such as batteries, whichgenerate a low level electrical current that increases permeation of adrug located in the working electrode. Frame 1652 also houses a screen1664, electronics 1666, including a controller and a timer, a speaker1668, an LED 1670, a dosing button 1672, and a transmitter, receiver, ortransceiver 1674 wirelessly connected to a separate electronic device1676 such as a cell phone, a watch, and the like. Electrodes 1658 and1660 may comprise a pad, a hydrogel, and the like, in which the workingelectrode contains the drug, and the passive electrode may contain asalt solution. For example, in anaphoresis, an anode is the workingelectrode, which is the electrode containing the drug to beadministered, and the second electrode (passive or return electrode) isthe cathode used to complete the electrical circuit and to initiatecurrent flow. When frame 1652 is positioned on a face 1678, workingelectrode 1658 held by arm 1656 is positioned on the skin at ABTTterminus 10, shown in dashed lines, and passive electrode 1660 ispositioned against the skin of a nose 1680, below ABTT terminus 10, asshown in FIG. 124.

FIG. 125 is a close-up view of a two arm structure 1682 in accordancewith an exemplary embodiment of the present disclosure, in which arm1656 with working electrode 1658 is configured to include a pad 1684containing a drug 1686. When a frame supporting arm 1656 is positionedon a subject or user's head, pad 1684 rests on ABTT terminus 10, withdrug 1686 being delivered to ABTT terminus 10 when activated, and arm1654 with passive electrode 1660 configured to include a pad 1688 withsalt solution and configured to be positioned away from ABTT terminus10. Two arm structure 1682 is configured to include a wire 1690extending through arm 1654 and a wire 1692 extending through arm 1656,which connect electrodes 1658 and 1660 to a power source and electronicshoused in the frame, such as those shown in FIG. 123.

It should be understood that frame 1652 can be configured to includeonly one arm 1694, as shown in FIG. 126, with arm 1694 housing bothactive electrode 1658 containing the drug and passive electrode 1660containing an inert solution, which are electrically connected by wire1692 and 1690 with power and electronics of frame 1652 (not shown). Itshould be understood that passive electrode 1660 can be located anywherein the frame 1652, as long as there is good contact with the skin, andby way of example, as shown in FIG. 127 passive electrode 1660 ispositioned at the end of a temple 1696 in apposition against auricularskin (not shown).

It should also be understood that an ABTT iontophoretic system can beintegrated in a patch 1700, as shown in FIG. 128, with patch 1700 beingpositioned on a face 1698 and housing active electrode 1658 and passiveelectrode 1660, a power source 1702 and electronics 1704. It shouldfurther be understood that the ABTT iontophoretic system can beintegrated in a nose clip 1706, as shown in FIG. 129, with nose clip1706 being positioned on a nose 1708 and housing active electrode 1658and passive electrode 1660, power source 1702, electronics 1704, and awireless device 1710 communicating with an external electronic device1712.

Although only the aspects discussed above have been described in detail,it should be understood that active means of transdermal delivery asdiscussed in detail above may also be adapted to be included in any ofthe support systems presented in the figures. In addition, it should beunderstood that, when sensing and regulatory means are employed, activeor passive transdermal delivery methods may be used to deliver the drugto the patient. For example, in the apparatus of FIGS. 71 and 72, oneside may comprise electronics and sensors needed to collect data andstore or transmit data, while the opposite side may be configured todeliver a drug transdermally using a passive method. As such, thetransdermal delivery is not necessarily regulated or controlled, butdata regarding drug levels in the patient's body may be collected andmonitored.

It should be understood that the embodiments may include a variety ofreservoirs or structures containing drugs, including single-layer,multi-layer, reservoir, matrix, and vapor. The structure may alsocomprise a support layer or backing and a single layer that containsboth the adhesive material and the drug to be released. The single layerpatch embodiment is preferred for immediate release of a drug.Multi-layer patches have multiple layers including a layer of the drugand adhesive and may be used for extended release of a drug. Someembodiments may include a porous layer. It should be understood that theembodiments can include a liner designed to extend delivery of a drugover a specified time period. Multiple-layer passive patches of thedisclosure are designed preferably for a timed release of the drug andto provide a constant delivery of a drug. A reservoir with liquidcompartment may be incorporated into a patch, clip, drug deliverymodules, eyeglasses frame, and any other embodiment of the presentdisclosure, with the liquid kept in a liquid compartment before release.It should be understood that patches and other embodiments of thepresent disclosure may include a matrix, which may contain semisolidmatrix solution with a drug, suspension with drugs, and the like. All ofthe embodiments can include a release liner, comprised preferably of athin sheet of plastic to protect the adhesive and drug layer.

Although permeation through ABTT terminus 10 is increased, and theapparatus of the present disclosure augments permeation of a drug, thedrug has a short and direct path to a blood vessel, and thus in generaldoes not require permeation enhancers, it should be understood that anypermeation enhancer can be used with any of the embodiments of presentdisclosure, and may include compounds that optimize the properties ofthe drug, and by way of example, but not limitation, includes the use ofprodrugs, liposomes, transferosomes, ethosomes, niosomes, nanoparticles,saturated and supersaturated solutions, eutectic systems, encapsulationin vesicles, cyclodextrin, and the like, or any compound that alters thephysical properties of the drug to increase fat solubility or thatoptimize transport in the stratum corneum. It should be understood thatany known alteration of a drug that will increase its permeability canbe used in any of the embodiments of the present disclosure. Directtreatment of the skin can also be used and is within the scope of theinvention, and may include hydration, lipid fluidization throughchemical penetration, keratin treatment, increased solubility in thestratum corneum, use of ointments such as paraffins, oils, waxes,water-in-oil emulsions that donate water to the skin. Any substance thatdisrupt or alter the stratum corneum may be used in the embodiments ofthe present disclosure and include lauryl lactate, oleic acid,turpentine, decylmethylsulphoxide, and the like. Any solvent can also beuse with the embodiments disclosed herein and include by way ofillustration, ethanol, propylene glycol, methyl pyrrolidone, and thelike.

It should also be understood that a variety of active device thatincrease permeation can be used with the embodiments of the presentdisclosure. Active types of transdermal delivery that use some form ofenergy to enhance permeation are, for example, iontophoresis, drivinghigh concentrations of charged molecules using a small direct current,as shown in FIGS. 123 to 129, sonophoresis, electroporation, and thelike. It should be understood that a frame of eyewear, goggles, andmasks of the present disclosure can include a sonophoresis device thatgenerate micro-vibrations in the skin of the ABTT terminus 10 andadjacent areas and veins 14, 16, 18, 20, and 22 using ultrasound wavesto increase lipid fluidity and create cavities, with subsequentadministration of medications, in accordance with the principles of thepresent disclosure. Other active apparatus can be integrated in theembodiments described herein, including electroporation with applicationof short electrical pulses to introduce a voltage gradient and createpores in ABTT terminus 10 and adjacent areas and veins 14, 16, 18, 20,and 22. Photomechanical devices generating waves includinglaser-generated stress waves to open pores at the ABTT terminus 10 andadjacent areas and veins 14, 16, 18, 20, and 22 can also be incorporatedin the frames and embodiments of the present disclosure, and are withinthe scope of the disclosure. The support structure, shown in otherembodiments housing electrodes, can be adapted to contain microneedlesor microprojection devices comprising solid or hollow needles, measuring100 μm or less in length that are adapted to penetrate just through thestratum corneum into the upper epidermis of the skin of ABTT terminus 10and adjacent areas and veins 14, 16, 18, 20, and 22 skin). Embodimentsand frames of the present disclosure can also include jet-propelledparticles that are applied against ABTT terminus 10 and adjacent areasand veins 14, 16, 18, 20, and 22 consisting of high-velocity micro jetof compressed gas carrying drug particles.

It should be further understood that an ABTT iontophoretic system andthermoelectric systems as described herein can be integrated in varietyof embodiments of the present invention including masks, goggles, hats,head mounted gear, and the like. It should also be understood that acombination of embodiments or a combination of components of eachembodiment are within the scope of the invention.

Although only the aspects discussed herein have been described indetail, it should be understood that active means of transdermaldelivery as discussed in detail herein may also be adapted to beincluded in any of the support systems presented in the figures. Inaddition, it should be understood that when sensing and regulatory meansare employed, active or passive transdermal delivery methods may be usedto deliver the drug to the patient.

While various embodiments of the disclosure have been shown anddescribed, it is understood that these embodiments are not limitedthereto. The embodiments may be changed, modified, and further appliedby those skilled in the art. Therefore, these embodiments are notlimited to the detail shown and described previously, but also includeall such changes and modifications.

1.-11. (canceled)
 12. A device configured to deliver a drugtransdermally to skin of a face feeding an Abreu brain thermal tunnel(ABTT), the device comprising: a first drug container; a firstthermoelectric device positioned adjacent the first drug container; asecond drug container; and a second thermoelectric device positionedadjacent the second drug container; wherein when the device ispositioned on the skin of the face, the temperature of the firstthermoelectric device and the temperature of the second thermoelectricdevice are adjusted to control delivery of a first drug from the firstdrug container and a second drug from the second drug container throughthe skin of the face.
 13. The device of claim 12, wherein the first drugcontainer is configured as an annulus positioned to surround the firstthermoelectric device.
 14. The device of claim 12, wherein the firstthermoelectric device is configured as an annulus, and the first drugcontainer is positioned in the annulus.
 15. The device of claim 12,wherein when the device is positioned on the skin of the face, thetemperature of the first thermoelectric device is adjusted to heat thefirst drug container to control the temperature of the first drug in thefirst drug container.
 16. The device of claim 12, wherein the device ispositioned on the skin of the face, and the temperature of the firstthermoelectric device is adjusted to heat the skin of the face to adjustthe permeability of the skin.
 17. The device of claim 12, wherein thefirst drug container and the first thermoelectric device are commonlysupported on an eyeglass frame.
 18. The device of claim 12, wherein thedevice is positioned on the skin of the face, and the temperature of thefirst thermoelectric device is adjusted to cool the skin of the face toreduce the permeability of the skin.
 19. The device of claim 17, whereinthe first drug container and the first thermoelectric device aresupported on a nose piece of the eyeglass frame.
 20. A device configuredto deliver a drug transdermally to skin, the device comprising: a firstdrug container; and a first thermoelectric device positioned adjacentthe first drug container, the first thermoelectric device configured tobe adjusted to control delivery of a first drug from the first drugcontainer to the skin.
 21. The device of claim 20, wherein the skin ispositioned over an Abreu brain thermal tunnel.
 22. The device of claim20, wherein the skin is positioned over one of a frontal vein, anangular vein, a supraorbital vein, and a superior palpebral vein. 23.The device of claim 20, wherein the skin is positioned over aretroauricular vein.
 24. The device of claim 20, wherein the first drugcontainer is configured as an annulus positioned to surround the firstthermoelectric device.
 25. The device of claim 20, wherein the firstthermoelectric device is configured as an annulus, and the first drugcontainer is positioned in the annulus.
 26. The device of claim 20,wherein the device is positioned on the skin, and the temperature of thefirst thermoelectric device is adjusted to heat the first drug containerto control the temperature of the first drug in the first drugcontainer.
 27. The device of claim 20, wherein the device is positionedon the skin, and the temperature of the first thermoelectric device isadjusted to heat the skin to adjust the permeability of the skin. 28.The device of claim 20, wherein the first drug container and the firstthermoelectric device are commonly supported on a glasses frame.
 29. Thedevice of claim 20, wherein the temperature of the first thermoelectricdevice is adjusted to cool the skin to reduce the permeability of theskin.
 30. The device of claim 28, wherein the first drug container andthe first thermoelectric device are supported on a nose piece of theglasses frame.